bims-meract 2025-03-30 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–03–30
28 papers selected by
Andrea Morandi, Università degli Studi di Firenze

Deletion of ENO1 sensitizes pancreatic cancer cells to gemcitabine via MYC/RRM1-mediated glycolysis.
SLC3A2-Mediated Lysine Uptake by Cancer Cells Restricts T cell Activity in Hepatocellular Carcinoma.
Apatinib combined with paclitaxel suppresses synergistically TNBC progression through enhancing ferroptosis susceptibility regulated SLC7A11/GPX4/ACSL4 axis.
Lactylation of LSD1 is an acquired epigenetic vulnerability of BRAFi/MEKi-resistant melanoma.
NAD+/SIRT1 pathway regulates glycolysis to promote oxaliplatin resistance in colorectal cancer.
ATOH8 confers the vulnerability of tumor cells to ferroptosis by repressing SCD expression.
LRPPRC confers enhanced oxidative phosphorylation metabolism in triple-negative breast cancer and represents a therapeutic target.
Protein lactylation in cancer: mechanisms and potential therapeutic implications.
Lipid-metabolism-focused CRISPR screens identify enzymes of the mevalonate pathway as essential for prostate cancer growth.
Inhibition of 6-phosphogluconate dehydrogenase suppresses esophageal squamous cell carcinoma growth and enhances the anti-tumor effects of metformin via the AMPK/mTOR pathway.
GATAD2B O-GlcNAcylation Regulates Breast Cancer Stem-like Potential and Drug Resistance.
LRRK2 reduces the sensitivity to TKI and PD-1 blockade in ccRCC via activating LPCAT1.
Dual inhibition of ATR and DNA-PKcs radiosensitizes ATM-mutant prostate cancer.
KRAS G12V mutation-selective requirement for ACSS2 in colorectal adenoma formation.
Multi-Omic Analysis Reveals a Lipid Metabolism Gene Signature and Predicts Prognosis and Chemotherapy Response in Thyroid Carcinoma.
ATP6AP1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy.
SUMOylation of RAD51 upregulates GOLPH3 expression and promotes cisplatin resistance in colon cancer cells by Sp1 transcriptional activity.
Arachidonic acid suppresses lung cancer cell growth and modulates lipid metabolism and the ERK/PPARγ signaling pathway.
Fatty acid synthase inhibitor cerulenin attenuates glioblastoma progression by reducing EMT and stemness phenotypes, inducing oxidative and ER stress response, and targeting PI3K/AKT/NF-κB axis.
A Genome-Wide Synthetic Lethal Screen Identifies Spermidine Synthase as a Target to Enhance Erdafitinib Efficacy in FGFR-Mutant Bladder Cancer.
Low dose Taxol causes mitochondrial dysfunction in actively respiring cancer cells.
Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement.
Programmed enhancement of endogenous iron-mediated lysosomal membrane permeabilization for tumor ferroptosis/pyroptosis dual-induction.
ZBTB6 promotes breast cancer progression by inhibiting ARHGAP6 transcription and modulating the STAT3 signaling pathway.
PI3Kβ functions as a protein kinase to promote cellular protein O-GlcNAcylation and acetyl-CoA production for tumor growth.
KIF4A facilitates oxaliplatin resistance and stemness in colon cancer by boosting glucose metabolism.
SOD2 is a regulator of proteasomal degradation promoting an adaptive cellular starvation response.
Knockdown of SLC7A5 inhibits malignant progression and attenuates oxaliplatin resistance in gastric cancer by suppressing glycolysis.

Sci Rep. 2025 Mar 22. 15(1): 9941

Deletion of ENO1 sensitizes pancreatic cancer cells to gemcitabine via MYC/RRM1-mediated glycolysis.

Yingpeng Lu, Hongqin Ma, Xiaoxiao Xiong, Yusheng Du, Li Liu, Ji Wang, Wenxing Zhao.

  Glycolysis is a critical metabolic pathway in cancer cells, fulfilling their energy requirements, supporting biosynthesis, maintaining redox balance, and enabling survival in hostile environments. Alpha-enolase (ENO1) has been identified as a key promoter of tumor progression through its involvement in glycolysis. This study aims to elucidate the relationship between ENO1, glycolysis, and gemcitabine sensitivity in pancreatic cancer (PC). The expression levels of ENO1 in PC were analyzed using the GEPIA2 database, Kaplan-Meier survival plots, and immunohistochemistry (IHC). To assess the impact of ENO1 on gemcitabine sensitivity, we manipulated ENO1 expression in PC cell lines through overexpression and silencing techniques. Subsequent analyses included flow cytometry assays, glucose uptake and lactate production measurements, and cytotoxicity assays. The underlying mechanisms by which ENO1 modulates gemcitabine sensitivity were explored using Western blotting (WB). ENO1 was found to be significantly overexpressed in PC tissues, and elevated ENO1 levels were associated with poorer prognosis in PC patients. Overexpression of ENO1 reduced the sensitivity of PC cells to gemcitabine, enhancing cell proliferation, migration, and invasion by altering the cell cycle and inhibiting apoptosis. Conversely, silencing ENO1 decreased glycolysis in PC cells and heightened their sensitivity to gemcitabine. Furthermore, glycolysis inhibition-achieved through ENO1 knockdown, glucose deprivation, or treatment with 2-Deoxy-D-glucose (2-DG)-further enhanced the susceptibility of PC cells to gemcitabine. Mechanistically, ENO1 was found to regulate the expression of gemcitabine resistance-related genes, particularly ribonucleotide reductase catalytic subunit M1 (RRM1), via MYC through the glycolytic pathway, thereby contributing to gemcitabine resistance. This study demonstrates that ENO1 plays a crucial role in PC progression and is closely linked to gemcitabine resistance through its regulation of the glycolytic pathway.

Keywords:  ENO1; Gemcitabine sensitivity; Glycolysis; PC; RRM1

DOI:  https://doi.org/10.1038/s41598-025-94319-0
Cancer Res. 2025 Mar 24.

SLC3A2-Mediated Lysine Uptake by Cancer Cells Restricts T cell Activity in Hepatocellular Carcinoma.

Yating Chang, Naizhen Wang, Shaopeng Li, Jiaqi Zhang, Yipeng Rao, Zilong Xu, Lu Li, Hongning Wu, Jun Chen, Yanhua Lin, Xiaoxuan Huang, Pingguo Liu, Jun Zhang, Yueting Liao, Chaolong Lin, Chenghao Huang, Ningshao Xia.

Abnormal amino acid metabolism supports cancer cell proliferation, invasion, and immune evasion in hepatocellular carcinoma (HCC). Previous research exploring amino acid metabolism in HCC has primarily focused on how metabolic reprogramming impacts tumor cells. Here, we focused on the role of amino acid metabolism dysregulation in the crosstalk between HCC and T cells. HCC cells disrupted lysine uptake in T cells, leading to impaired T cell immunity. Lysine deprivation decreased STAT3 levels in T cells, inhibiting T cell proliferation and effector function and ultimately promoting tumor progression. Mechanistically, HCC cells outcompeted T cells for lysine by expressing high levels of the lysine transporter SLC3A2. Clinically, elevated SLC3A2 expression correlated with poor survival and was linked to dysregulated T cell functional gene signatures in HCC patients. Furthermore, the multikinase inhibitor lenvatinib induced a c-Myc-SLC3A2 regulatory axis that limited the efficacy of lenvatinib treatment. Lysine supplementation enhanced tumor sensitivity to combined treatment with lenvatinib and anti-PD-1 immunotherapy. These findings suggest that lysine supplementation is a potential therapeutic strategy for treating HCC and enhancing the sensitivity of HCC to tyrosine kinase inhibitors and immune checkpoint blockade.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3180
Cell Signal. 2025 Mar 20. pii: S0898-6568(25)00173-1. [Epub ahead of print]131 111760

Apatinib combined with paclitaxel suppresses synergistically TNBC progression through enhancing ferroptosis susceptibility regulated SLC7A11/GPX4/ACSL4 axis.

Xiaoxia Ma, Di Cao, Yan Zhang, Xiaoyun Ding, Zhiqiang Hu, Jing Wang.

  Triple-negative breast cancer (TNBC) is highly heterogeneous, often leading to resistance to chemotherapy agents like paclitaxel (PTX) and resulting in suboptimal outcomes. The anti-angiogenic agent apatinib not only enhances chemotherapy sensitivity but also involves in regulating ferroptosis. However, the potential of combining apatinib with PTX to improve treatment efficacy in refractory TNBC by increasing tumor cell susceptibility to ferroptosis remains elusive. This study aims to elucidate whether inducing ferroptosis participates in the beneficial effects of apatinib combined with PTX to synergistically suppress TNBC. Herein, we demonstrated that the coadministration of apatinib and PTX exerted significant inhibitory effects on both primary tumor progression and distant metastases to pulmonary and hepatic tissues in TNBC-bearing murine models. Transcriptomic and proteomic analyses indicated that ferroptosis induction is a key mechanism by which the drug combination suppresses TNBC, as evidenced by a marked downregulation of SLC7A11, GPX4, NRF2, and FTH1, and a significant upregulation of ACSL4. In vitro, the combination of 5 μM apatinib and 8 nM PTX synergistically inhibited tumor cell proliferation, migration, and invasion. Notably, the combination therapy markedly augmented ferroptosis in tumor cells through the regulation of the SLC7A11/GPX4/ACSL4 axis, leading to increased intracellular iron accumulation and lipid peroxide generation, concomitant with a reduction in GSH levels. The effect of apatinib combined with PTX on enhancing ferroptosis susceptibility could be exploited as a combination treatment regimen for future TNBC therapy.

Keywords:  Apatinib; Ferroptosis; GPX4; Paclitaxel; TNBC

DOI:  https://doi.org/10.1016/j.cellsig.2025.111760
Dev Cell. 2025 Mar 20. pii: S1534-5807(25)00121-2. [Epub ahead of print]

Lactylation of LSD1 is an acquired epigenetic vulnerability of BRAFi/MEKi-resistant melanoma.

Aicun Li, Zhicheng Gong, Yuhan Long, Yuanpei Li, Chen Liu, Xiao Lu, Qing Li, Xiaoniu He, Hezhe Lu, Kaichun Wu, Yongzhan Nie, Jing Tan, Jing Ye, Han You.

  BRAFV600E mutant melanomas treated with BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) almost invariably develop drug resistance, accompanied by restored glucose metabolism. How resumed glycolysis controls acquired resistance remains unknown. Here, we identify that lysine-specific demethylase 1 (LSD1) lactylation, induced by re-accumulated lactate in both human and murine BRAFi/MEKi-resistant melanoma cells, selectively drives survival via epigenetic reprogramming. Mechanistically, lactylation of LSD1 promotes its interaction with Fos-related antigen 1 (FosL1), preventing its degradation by E3 ligase tripartite-motif-containing protein 21 (TRIM21) and selectively enhancing its genomic enrichment. We further demonstrate that lactylated LSD1 co-directs gene transcription with FosL1 to repress ferroptosis via interfering with transferrin receptor protein 1 (TFRC)-mediated iron uptake. LSD1 inhibition activates ferroptosis, resulting in drastic regression of drug-resistant murine melanoma when combined with immunotherapy. Our results highlight a crucial role of metabolic rewiring-induced epigenetic reprogramming as a bypass resistance mechanism in BRAFi/MEKi-resistant melanoma, providing a therapeutically actionable strategy to overcome resistance to targeted therapy and immunotherapy.

Keywords:  BRAFV600E melanoma; FosL1; LSD1; epigenetic reprogramming; ferroptosis; immunotherapy; lactylation; metabolic reprogramming; targeted-therapy resistance; ubiquitination

DOI:  https://doi.org/10.1016/j.devcel.2025.02.016
World J Gastroenterol. 2025 Mar 21. 31(11): 100785

NAD+/SIRT1 pathway regulates glycolysis to promote oxaliplatin resistance in colorectal cancer.

Ya-Ru Niu, Mi-Dan Xiang, Wen-Wei Yang, Yu-Ting Fang, Hai-Li Qian, Yong-Kun Sun.

   BACKGROUND: Glycolysis provides growth advantages and leads to drug resistance in colorectal cancer (CRC) cells. SIRT1, an NAD+-dependent deacetylase, regulates various cellular processes, and its upregulation results in antitumor effects. This study investigated the role of SIRT1 in metabolic reprogramming and oxaliplatin resistance in CRC cells.
AIM: To investigate the role of SIRT1 in metabolic reprogramming and overcoming oxaliplatin resistance in CRC cells.
METHODS: We performed transcriptome sequencing of human CRC parental cells and oxaliplatin-resistant cells to identify differentially expressed genes. Key regulators were identified via the LINCS database. NAD+ levels were measured by flow cytometry, and the effects of SIRT1 on oxaliplatin sensitivity were assessed by MTS assays, colony formation assays, and xenograft models. Glycolytic function was measured using Western blot and Seahorse assays.
RESULTS: Salermide, a SIRT1 inhibitor, was identified as a candidate compound that enhances oxaliplatin resistance. In oxaliplatin-resistant cells, SIRT1 was downregulated, whereas γH2AX and PARP were upregulated. PARP activation led to NAD+ depletion and SIRT1 inhibition, which were reversed by PARP inhibitor treatment. The increase in SIRT1 expression overcame oxaliplatin resistance, and while SIRT1 inhibition increased glycolysis, the increase in SIRT1 inhibited glycolysis in resistant CRC cells, which was characterized by reduced expression of the glycolytic enzymes PKM2 and LDHA, as well as a decreased extracellular acidification rate. The PKM2 inhibitor shikonin inhibited glycolysis and reversed oxaliplatin resistance induced by SIRT1 inhibition.
CONCLUSION: SIRT1 expression is reduced in oxaliplatin-resistant CRC cells due to PARP activation, which in turn increases glycolysis. Restoring SIRT1 expression reverses oxaliplatin resistance in CRC cells, offering a promising therapeutic strategy to overcome drug resistance.

Keywords:  Chemotherapy resistance; Colorectal cancer; Glycolysis; NAD+; SIRT1

DOI:  https://doi.org/10.3748/wjg.v31.i11.100785
Cell Death Differ. 2025 Mar 25.

ATOH8 confers the vulnerability of tumor cells to ferroptosis by repressing SCD expression.

Huixiang Xiao, Xinxing Du, Huan Hou, Wenyun Guo, Zhenkeke Tao, Shijia Bao, Zhenzhen Wen, Nan Jing, Wei-Qiang Gao, Baijun Dong, Yu-Xiang Fang.

Emerging evidence indicates that transcriptional regulation plays pivotal roles in modulating cellular vulnerability to ferroptosis. However, the intricate mechanisms governing these processes remain poorly understood. In this study, we identify ATOH8, a basic helix-loop-helix (bHLH) transcription factor, as a key player in ferroptosis regulation. ATOH8 is significantly upregulated in tumor cells following treatment with a ferroptosis inducer. Overexpression of ATOH8 increases the susceptibility of tumor cells to ferroptosis, while deletion of ATOH8 promotes ferroptosis evasion. Mechanistically, ATOH8 confers the sensitivity of tumor cells to ferroptosis by suppressing the transcription of stearoyl-CoA desaturase (SCD). Additionally, another bHLH family member, TCF3, is found to functions as a co-factor with ATOH8 by forming a TCF3-ATOH8 transcriptional repressive complex that suppresses SCD transcription. Furthermore, searching for upstream element reveals that EZH2 epigenetically suppresses ATOH8 expression by promoting DNA methylation in the ATOH8 promoter region and increasing the level of H3K27 me3. Importantly, pharmacological inhibition of EZH2 in a combined with a ferroptosis inducer markedly impedes tumor growth both in vitro and in vivo. Collectively, our study elucidates a molecular link between ferroptosis and epigenetic and transcriptional regulation, highlighting the potential of EZH2 and ATOH8 as therapeutic targets for cancer treatment.

DOI: https://doi.org/10.1038/s41418-025-01482-y
J Transl Med. 2025 Mar 25. 23(1): 372

LRPPRC confers enhanced oxidative phosphorylation metabolism in triple-negative breast cancer and represents a therapeutic target.

Qiqi Xue, Wenxi Wang, Jie Liu, Dachi Wang, Tianyu Zhang, Tingting Shen, Xiangsheng Liu, Xiaojia Wang, Xiying Shao, Wei Zhou, Xiaohong Fang.

   BACKGROUND: Triple-negative breast cancer (TNBC) is a highly malignant tumor that requires effective therapeutic targets and drugs. Oxidative phosphorylation (OXPHOS) is a metabolic vulnerability of TNBC, but the molecular mechanism responsible for the enhanced OXPHOS remains unclear. The current strategies that target the electronic transfer function of OXPHOS cannot distinguish tumor cells from normal cells. Investigating the mechanism underlying OXPHOS regulation and developing corresponding therapy strategies for TNBC is of great significance.
METHODS: Immunohistochemistry and sequencing data reanalysis were used to investigate LRPPRC expression in TNBC. In vitro and in vivo assays were applied to investigate the roles of LRPPRC in TNBC progression. RT-qPCR, immunoblotting, and Seahorse XF assay were used to examine LRPPRC's functions in the expression of OXPHOS subunits and energy metabolism. In vitro and in vivo functional assays were used to test the therapeutic effect of gossypol acetate (GAA), a traditional gynecological drug, on LRPPRC suppression and OXPOHS inhibition.
RESULTS: LRPPRC was specifically overexpressed in TNBC. LRPPRC knockdown suppressed the proliferation, metastasis, and tumor formation of TNBC cells. LRPPRC enhanced OXPHOS metabolism by increasing the expression of OXPHOS complex subunits encoded by the mitochondrial genome. GAA inhibited OXPHOS metabolism by directly binding LRPPRC, causing LRPPRC degradation, and downregulating the expression of OXPHOS complex subunits encoded by the mitochondrial genome. GAA administration suppressed TNBC cell proliferation, metastasis in vitro, and tumor formation in vivo.
CONCLUSIONS: This work demonstrated a new regulatory pathway of TNBC to promote the expression of mitochondrial genes by upregulating the nuclear gene LRPPRC, resulting in increased OXPHOS. We also suggested a promising therapeutic target LRPPRC for TNBC, and its inhibitor, the traditional gynecological medicine GAA, presented significant antitumor activity.

Keywords:  Gossypol acetate; Oxidative phosphorylation; Triple-negative breast cancer

DOI:  https://doi.org/10.1186/s12967-024-05946-6
Exp Mol Med. 2025 Mar 24.

Protein lactylation in cancer: mechanisms and potential therapeutic implications.

Hyunsoo Rho, Nissim Hay.

Increased glycolysis, which leads to high lactate production, is a common feature of cancer cells. Recent evidence suggests that lactate plays a role in the post-translational modification of histone and nonhistone proteins via lactylation. In contrast to genetic mutations, lactylation in cancer cells is reversible. Thus, reversing lactylation can be exploited as a pharmacological intervention for various cancers. Here we discuss recent advances in histone and nonhistone lactylation in cancer, including L-, D- and S-lactylation, as well as alanyl-tRNA synthetase as a novel lactyltransferase. We also discuss potential approaches for targeting lactylation as a therapeutic opportunity in cancer treatment.

DOI: https://doi.org/10.1038/s12276-025-01410-7
Cell Rep. 2025 Mar 26. pii: S2211-1247(25)00241-4. [Epub ahead of print]44(4): 115470

Lipid-metabolism-focused CRISPR screens identify enzymes of the mevalonate pathway as essential for prostate cancer growth.

Gio Fidelito, Izabela Todorovski, Leonie Cluse, Stephin J Vervoort, Renea A Taylor, Matthew J Watt.

  Dysregulated lipid metabolism plays an important role in prostate cancer, although the understanding of the essential regulatory processes in tumorigenesis is incomplete. We employ a CRISPR-Cas9 screen using a custom human lipid metabolism knockout library to identify essential genes for prostate cancer survival. Screening in three prostate cancer cell lines reveals 63 shared dependencies, with enrichment in terpenoid backbone synthesis and N-glycan biosynthesis. Independent knockout of key genes of the mevalonate pathway reduces cell proliferation. Further investigation focuses on NUS1, a subunit of cis-prenyltransferase required for dolichol synthesis. NUS1 knockout decreases tumor growth in vivo and viability in patient-derived xenograft (PDX)-derived organoids. Mechanistic studies reveal that loss of NUS1 promotes oxidative stress, lipid peroxidation and ferroptosis sensitivity, endoplasmic reticulum (ER) stress, and G1 cell-cycle arrest, and it dampens androgen receptor (AR) signaling, collectively leading to growth arrest. This study highlights the critical role of the mevalonate-dolichol-N-glycan biosynthesis pathway, particularly NUS1, in prostate cancer survival and growth.

Keywords:  CP: Cancer; CP: Metabolism; CRISPR screen; cancer metabolism; lipid metabolism; prostate cancer

DOI:  https://doi.org/10.1016/j.celrep.2025.115470
Mol Cancer. 2025 Mar 26. 24(1): 97

Inhibition of 6-phosphogluconate dehydrogenase suppresses esophageal squamous cell carcinoma growth and enhances the anti-tumor effects of metformin via the AMPK/mTOR pathway.

Bei Wang, Zixuan Wang, Zini Zhou, Gui Liu, Zhenyuan Jiang, Mingyue Zheng, Wei Geng.

  Metabolic reprogramming plays a pivotal role in the development and progression of tumors. Tumor cells rely on glycolysis as their primary energy production pathway and effectively utilize biomolecules generated by the pentose phosphate pathway (PPP) for efficient biosynthesis. However, the role of 6-phosphogluconate dehydrogenase (6PGD), a crucial enzyme in the PPP, remains unexplored in esophageal squamous cell carcinoma (ESCC). In this study, we observed a significant upregulation of 6PGD expression in ESCC tissues, which correlated with an unfavorable prognosis among patients. The experiments demonstrated that knockdown of 6PGD induces oxidative stress and suppresses ESCC cell proliferation. Mechanistically, this is achieved through AMPK activation and subsequent inhibition of downstream mTOR phosphorylation. Moreover, physcion has been found to inhibit 6PGD activity and exert its anti-ESCC effect via the AMPK/mTOR pathway. Subsequently, we conducted both in vitro and in vivo experiments to validate the anticancer efficacy of combining metformin, an AMPK activator, with physcion. The results demonstrated a significantly enhanced inhibition of ESCC growth. This study elucidates the impact of 6PGD on ESCC cell proliferation along with its underlying molecular mechanisms, highlighting its potential as a therapeutic target for ESCC. Furthermore, we investigated a novel approach for improved anti-tumor therapy involving physcion and metformin. These findings will contribute new insights to clinical treatment strategies for ESCC while providing a theoretical foundation for developing molecular targeted therapies.

Keywords:  6-phosphogluconate dehydrogenase; Esophageal squamous cell carcinoma; Metformin; Pentose phosphate pathway; Physcion

DOI:  https://doi.org/10.1186/s12943-025-02302-0
Cells. 2025 Mar 08. pii: 398. [Epub ahead of print]14(6):

GATAD2B O-GlcNAcylation Regulates Breast Cancer Stem-like Potential and Drug Resistance.

Giang Le Minh, Jessica Merzy, Emily M Esquea, Nusaiba N Ahmed, Riley G Young, Ryan J Sharp, Tejsi T Dhameliya, Bernice Agana, Mi-Hye Lee, Jennifer R Bethard, Susana Comte-Walters, Lauren E Ball, Mauricio J Reginato.

  The growth of breast tumors is driven and controlled by a subpopulation of cancer cells resembling adult stem cells, which are called cancer stem-like cells (CSCs). In breast cancer, the function and maintenance of CSCs are influenced by protein O-GlcNAcylation and the enzyme responsible for this post-translational modification, O-GlcNAc transferase (OGT). However, the mechanism of CSCs regulation by OGT and O-GlcNAc cycling in breast cancer is still unclear. Analysis of the proteome and O-GlcNAcome, revealed GATAD2B, a component of the Nucleosome Remodeling and Deacetylase (NuRD) complex, as a substrate regulated by OGT. Reducing GATAD2B genetically impairs mammosphere formation, decreases expression of self-renewal factors and CSCs population. O-GlcNAcylation of GATAD2B at the C-terminus protects GATAD2B from ubiquitination and proteasomal degradation in breast cancer cells. We identify ITCH as a novel E3 ligase for GATAD2B and show that targeting ITCH genetically increases GATAD2B levels and increases CSCs phenotypes. Lastly, we show that overexpression of wild-type GATAD2B, but not the mutant lacking C-terminal O-GlcNAc sites, promotes mammosphere formation, expression of CSCs factors and drug resistance. Together, we identify a key role of GATAD2B and ITCH in regulating CSCs in breast cancer and GATAD2B O-GlcNAcylation as a mechanism regulating breast cancer stem-like populations and promoting chemoresistance.

Keywords:  GATAD2B; NuRD; O-GlcNAc; OGT; cancer; cancer stem cell; chemoresistance; signaling

DOI:  https://doi.org/10.3390/cells14060398
Oncogene. 2025 Mar 22.

LRRK2 reduces the sensitivity to TKI and PD-1 blockade in ccRCC via activating LPCAT1.

Yulong Hong, Wei Li, Zhuo Xing, Minghao Lu, Tianyu Tang, Liang Zhu, Wei Xiong, Huan Zhang, Wentao Liu, Shangqing Ren.

Tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) combination therapy is emerging as a major therapeutic strategy for advanced clear cell renal cell carcinoma (ccRCC). To define the druggable targets for improvement of TKI and ICI combination therapy in ccRCC, we analyzed a commercial protein kinase inhibitor dataset and a public ccRCC dataset and identified LRRK2 as a potential candidate that can be targeted by a small molecule inhibitor. We demonstrated that LRRK2 was transcriptionally upregulated by HIF2A and enabled to drive proliferation of ccRCC cells in a manner independent of its kinase activity. LRRK2 inhibits the RBX1-mediated degradation of lipid metabolism modulator LPCAT1 to reducing the sensitivity to TKI and PD-1 blockade in ccRCC. Specifically, LRRK2/LPCAT1 upregulated IL-1β expression levels through AKT and also increased IL-1β shearing by activating inflammasome. To target the kinase-independent activity of LRRK2, we developed an LR-protac and showed that LR-protac decreased LRRK2 protein level and enhanced the antitumor effect of PD-1 blockade and TKI in ccRCC. These data indicate that LRRK2 is a viable target for improvement of the efficacy of PD-1 blockade and TKI in ccRCC.

DOI: https://doi.org/10.1038/s41388-025-03289-0
Oncogene. 2025 Mar 21.

Dual inhibition of ATR and DNA-PKcs radiosensitizes ATM-mutant prostate cancer.

Mia Hofstad, Andrea Woods, Karla Parra, Zoi E Sychev, Alice Mazzagatti, Xiaofang Huo, Lan Yu, Collin Gilbreath, Wei-Min Chen, Anthony J Davis, Peter Ly, Justin M Drake, Ralf Kittler.

In advanced castration resistant prostate cancer (CRPC), mutations in the DNA damage response (DDR) gene ataxia telangiectasia mutated (ATM) are common. While poly(ADP-ribose) polymerase inhibitors are approved in this context, their clinical efficacy remains limited. Thus, there is a compelling need to identify alternative therapeutic avenues for ATM mutant prostate cancer patients. Here, we generated matched ATM-proficient and ATM-deficient CRPC lines to elucidate the impact of ATM loss on DDR in response to DNA damage via irradiation. Through unbiased phosphoproteomic screening, we unveiled that ATM-deficient CRPC lines maintain dependence on downstream ATM targets through activation of ATR and DNA-PKcs kinases. Dual inhibition of ATR and DNA-PKcs effectively inhibited downstream γH2AX foci formation in response to irradiation and radiosensitized ATM-deficient lines to a greater extent than either ATM-proficient controls or single drug treatment. Further, dual inhibition abrogated residual downstream ATM pathway signaling and impaired replication fork dynamics. To circumvent potential toxicity, we leveraged the RUVBL1/2 ATPase inhibitor Compound B, which leads to the degradation of both ATR and DNA-PKcs kinases. Compound B effectively radiosensitized ATM-deficient CRPC in vitro and in vivo, and impacted replication fork dynamics. Overall, dual targeting of both ATR and DNA-PKcs is necessary to block DDR in ATM-deficient CRPC, and Compound B could be utilized as a novel therapy in combination with irradiation in these patients.

DOI: https://doi.org/10.1038/s41388-025-03343-x
Cell Rep. 2025 Mar 24. pii: S2211-1247(25)00215-3. [Epub ahead of print]44(4): 115444

KRAS G12V mutation-selective requirement for ACSS2 in colorectal adenoma formation.

Konstantin Budagyan, Alexa C Cannon, Adam Chatoff, Dorothy Benton, Alison M Kurimchak, Daniela Araiza-Olivera, Anastasiia Gerasimova, Nathaniel W Snyder, James S Duncan, Cristina Uribe-Alvarez, Jonathan Chernoff.

  Oncogenic KRAS mutations are prevalent in colorectal cancer (CRC) and linked to poor prognosis and therapeutic resistance. Emerging evidence suggests that specific KRAS mutations differentially influence treatment responses. In this study, we generate isogenic Apc-null mouse colon epithelial cells with four common KRAS mutations. Transcriptomic and proteomic analyses reveal significant enrichment of cholesterol and lipid metabolism pathways in KRAS G12V cells, driven by increased SREBP1 expression and mTORC1 activation. Furthermore, KRAS G12V cells exhibit elevated ACSS2 expression and greater dependence on ACSS2 for proliferative advantage compared to other mutants. Inhibition of ACSS2 uniquely sensitizes KRAS G12V cells to MEK inhibition, highlighting a distinct therapeutic vulnerability. Finally, ACSS2 plays a critical role in early KRAS G12V adenoma development, unlike in KRAS G12D adenomas. These findings highlight mutation-specific metabolic reprogramming in KRAS-driven CRC and identify ACSS2 as a potential therapeutic target.

Keywords:  ACSS2; CP: Cancer; KRAS; acetate; acetyl-CoA; acetylation; adenoma; colorectal cancer; drug resistance; metabolism; signal transduction

DOI:  https://doi.org/10.1016/j.celrep.2025.115444
Cancer Med. 2025 Mar;14(6): e70819

Multi-Omic Analysis Reveals a Lipid Metabolism Gene Signature and Predicts Prognosis and Chemotherapy Response in Thyroid Carcinoma.

Yuqin Tu, Yanchen Chen, Linlong Mo, Guiling Yan, Jingling Xie, Xinyao Ji, Shu Chen, Changchun Niu, Pu Liao.

   OBJECTIVE: Lipid metabolic reprogramming is closely intertwined with the development and progression of thyroid carcinoma (TC); however, its specific mechanism remains elusive. This study aimed to investigate the association between lipid metabolism and TC progression.
METHODS: We employed liquid chromatography-mass spectrometry (LC/MS) for an untargeted metabolomics analysis, comparing 12 TC patients and 12 healthy controls (HC). Additionally, we conducted the screening of differentially expressed genes (DEGs) and identified differentially expressed lipid metabolism genes (LMGs). Multi-omic findings related to lipid metabolism were integrated to establish a prognostic risk model. The resulting risk score stratified TC patients into high- and low-risk groups. Overall survival (O.S.) was assessed using Kaplan-Meier (K-M) analysis. The immune landscape was evaluated using the CIBERSORT algorithm, and chemotherapeutic response was predicted utilizing the "pRRophetic" R package.
RESULTS: Our metabolomic analysis revealed heightened lipid metabolic activity in TC, corroborated by similar findings in transcriptomic analysis. Multi-omic analysis identified key LMGs (FABP4, PPARGC1A, AGPAT4, ALDH1A1, TGFA, and GPAT3) associated with fatty acids and glycerophospholipids metabolism. A novel risk model, incorporating these LMGs, confirmed significantly worse O.S. (p = 0.0045) in the high-risk group based on TCGA_THCA. Furthermore, high-risk TC patients exhibited lower immune cell infiltration, and predictive outcomes indicated the efficacy of potential therapeutic drugs across risk groups.
CONCLUSION: This multi-omic analysis underscores the potential utility of the lipid metabolism risk model in guiding clinical treatment and improving outcomes for TC patients.

Keywords:  chemotherapy response; lipid metabolism genes; multi‐omic analysis; prognosis; thyroid carcinoma

DOI:  https://doi.org/10.1002/cam4.70819
Cell Death Dis. 2025 Mar 25. 16(1): 201

ATP6AP1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy.

Zhengwei Yan, Aidi Huang, Dongwen Ma, Chenao Hong, Shengmiao Zhang, Luling He, Hai Rao, Shiwen Luo.

Autophagy is a highly conserved cellular process essential for maintaining cellular homeostasis and influencing cancer development. Lysosomal acidification and autophagosome-lysosome fusion are two important steps of autophagy degradation that are tightly regulated. Although many key proteins that regulate these two events have been identified, the effector proteins that co-regulate both steps remain to be explored. ATP6AP1, an accessory subunit of V-ATPase, plays a critical role in the assembly and regulation of V-ATPase. However, the function of ATP6AP1 in autophagy remains unknown, and the role of ATP6AP1 in cancer is still poorly understood. In this study, we found that ATP6AP1 is overexpressed in luminal breast cancer tissues and promotes the proliferation and tamoxifen resistance of luminal breast cancer cells both in vitro and in vivo. We also observed that high ATP6AP1 expression correlates with poor overall patient survival. Our research further revealed that ATP6AP1 enhances tamoxifen resistance by activating autophagy. Mechanistically, ATP6AP1 promotes autophagy by regulating both lysosomal acidification and autophagosome-lysosome fusion. Remarkably, ATP6AP1 induces lysosomal acidification through the regulation of V-ATPase assembly and facilitates autophagosome-lysosome fusion by enhancing the interaction between Rab7 and the HOPS complex. Together, our studies identify ATP6AP1 as a crucial regulator of autophagy, potentially serving as a valuable prognostic marker or therapeutic target in human luminal breast cancer.

DOI: https://doi.org/10.1038/s41419-025-07534-y
Biochem Pharmacol. 2025 Mar 22. pii: S0006-2952(25)00150-9. [Epub ahead of print]236 116888

SUMOylation of RAD51 upregulates GOLPH3 expression and promotes cisplatin resistance in colon cancer cells by Sp1 transcriptional activity.

Yuze Wu, Bingchen Lin, Zhiyong Xie, Jingshan Huang, Yi Qiu, Xiaojing Chen, Zhongshi Hong, Chengzhi Qiu.

  Platinum-based chemotherapy is a first-line treatment for colon cancer. Previous studies have shown that Golgi phosphoprotein 3 (GOLPH3) overexpression drives platinum resistance in colon cancer and is associated with DNA damage repair (DDR). However, the mechanism by which DDR induces GOLPH3 expression remains unclear. This study investigates how RAD51 recombinase (RAD51) SUMOylation upregulates GOLPH3 expression and promotes platinum resistance in colon cancer. In DDP-resistant colon adenocarcinoma (COAD) cells, Specificity protein 1 (Sp1) and GOLPH3 were overexpressed, while N-myc downstream regulated 1 (NDRG1) was downregulated. Knockdown of Sp1 or GOLPH3 increased NDRG1 expression, inhibited COAD cell proliferation, promoted cell apoptosis, and enhanced cell sensitivity to cisplatin (DDP). Immunohistochemistry (IHC) and bioinformatics analyses of COAD tissues revealed a positive correlation between RAD51, SUMO1 and Sp1 expression. Sp1 was found to increase DDP resistance by transcriptionally activating GOLPH3 expression. RAD51 was SUMOylated by SUMO1 at the K57 site, and this modification decreased COAD cell sensitivity to DDP by enhancing Sp1 transcriptional activity. Furthermore, RAD51 overexpression led to upregulation of GOLPH3 and downregulation of NDRG1, promoting cell proliferation, inhibiting apoptosis, and increasing resistance to DDP. Conversely, the RAD51 mutant did not affect GOLPH3 expression or platinum resistance in vivo and in vitro. In conclusion, RAD51 SUMOylation at the K57 site enhances Sp1 transcriptional activity, thereby reducing colon cancer cell sensitivity to DDP by regulating GOLPH3 and NDRG1 expression. This discovery elucidates the molecular mechanism of DDR-induced GOLPH3 upregulation, offering a new perspective for overcoming DDP resistance in colon cancer.

Keywords:  Colon cancer; DDP resistance; GOLPH3; RAD51; SUMOylation; Sp1

DOI:  https://doi.org/10.1016/j.bcp.2025.116888
Lipids Health Dis. 2025 Mar 27. 24(1): 114

Arachidonic acid suppresses lung cancer cell growth and modulates lipid metabolism and the ERK/PPARγ signaling pathway.

Lin Wang, Lanlan Wei, Xueling Chen, Jiali Xiong.

  Lung cancer remains the leading cause of cancer-related mortality worldwide, necessitating the development of new treatment strategies. Arachidonic acid (ARA), a polyunsaturated fatty acid, shows promise in cancer therapy due to its potential anti-tumor effects, although its role in lung cancer remains unclear. This study investigated the effects and underlying mechanism of ARA on A549 and NCI-H1299 lung cancer cells. In vitro assays were used to assess cell viability, apoptosis, colony formation, lipid droplet formation, and changes in cellular lipid content. ARA dose-dependently suppressed cell viability, facilitated apoptosis, and suppressed colony formation in both lung cancer cell lines. Network pharmacology analysis was performed to identify potential gene targets and pathways, uncovering 61 overlapping genes between ARA and lung cancer-related targets, with mitogen-activated protein kinase 1 (MAPK1) emerging as a key gene. Enrichment analyses suggested that the effects of ARA might be mediated through lipid metabolism and the extracellular signal-regulated kinase (ERK)/peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway. In both lung cancer cell lines, ARA treatment inhibited lipid droplet formation and decreased the cellular lipids. Immunoblotting further confirmed that ARA treatment significantly increased ERK phosphorylation while reducing PPARγ and fatty acid synthase (FASN) protein levels. In vitro experiments using GW9662, a PPARγ antagonist, confirmed that inhibiting lipid droplet formation impairs lung cancer cell viability and promotes apoptosis. Furthermore, in vivo experiments demonstrated that ARA significantly reduced tumor size and weight in a lung cancer xenograft model, further validating its anti-tumor effects. The potential of ARA as a therapeutic agent for lung cancer might involve lipid metabolism and relevant signaling pathways. A future study exploring the full therapeutic potential of ARA and underlying mechanisms in lung cancer is needed.

Keywords:  Arachidonic acid (ARA); Lipid metabolism; Lung cancer; Mitogen-activated protein kinase 1 (MAPK1); The extracellular signal-regulated kinase (ERK)/peroxisome proliferator-activated receptor gamma (PPARγ) pathway

DOI:  https://doi.org/10.1186/s12944-025-02490-0
Med Oncol. 2025 Mar 25. 42(5): 136

Fatty acid synthase inhibitor cerulenin attenuates glioblastoma progression by reducing EMT and stemness phenotypes, inducing oxidative and ER stress response, and targeting PI3K/AKT/NF-κB axis.

Murat Pekmez, Şefika Beyza Mete, Yunus Aksüt, İrem Öğütcü, Fatma Nur Baştürk, Yusuf Can Gerçek, Aslıhan Şengelen.

  Targeting cellular metabolism is becoming a critical approach for stopping cancer progression. Limited information is available regarding the effects of inhibiting the lipogenic enzyme fatty acid synthase (FASN) in glioblastoma (GB) cells (grade-IV-astrocytoma), which have high invasion and low response to standard treatments. Herein, we used cerulenin (CER) to inhibit FASN. CER treatments (3.6 μg/mL/48 h and 5.55 μg/mL/48 h indicate IC20 and IC50 values, respectively) led to a dose- and time-dependent decrease in the viability of the U-87MG human GB cells. A significant decrease was detected in the levels of fatty acids, including palmitic acid, determined by GS-MS analysis. FASN inhibition attenuated cell motility, 2D and 3D-clonogenic survival, and cell differentiation characteristics (related markers of epithelial-mesenchymal transition/EMT and stemness). Moreover, treatments caused mitochondrial membrane potential (MMP) collapse and increased intracellular reactive oxygen species (ROS) levels. Protein aggregates and ER stress in the cells also increased. Remarkably, despite increased Hsp70 and p-HSF1 levels against induced cellular stress, CER promoted markedly autophagy and apoptosis. The network pharmacology approach revealed that protein and lipid kinases are crucial targets in cell signaling, and PI3K, AKT, and NF-κB levels were confirmed by immunoblotting. The results demonstrated for the first time that inhibiting FA production and FASN function induces cell death through ROS generation and ER stress while simultaneously reducing the motility and aggressiveness of U-87MG human glioblastoma cells by attenuating EMT and stemness phenotypes. Therefore, blocking lipid metabolism using CER may be considered as a good candidate for GB therapeutic option.

Keywords:  Anti-cancer effect; Cellular stress response; Cerulenin (CER); Fatty acid synthase (FASN) inhibitor; Glioblastoma

DOI:  https://doi.org/10.1007/s12032-025-02697-2
Cancer Res. 2025 Mar 24.

A Genome-Wide Synthetic Lethal Screen Identifies Spermidine Synthase as a Target to Enhance Erdafitinib Efficacy in FGFR-Mutant Bladder Cancer.

Yanchao Yu, Xincheng Gao, Huayuan Zhao, Jiayin Sun, Miao Wang, Xing Xiong, Junping Li, Chao Huang, Hui Zhang, Guosong Jiang, Xingyuan Xiao.

Mutations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic bladder cancer. The development of erdafitinib, a pan-FGFR inhibitor, provided a significant therapeutic advance in bladder cancer, but resistance still limits its efficacy. In this study, we performed an unbiased whole-genome CRISPR-Cas9 synthetic lethal screen on FGFR-mutant bladder cancer cell lines treated with erdafitinib and identified spermidine synthase (SRM) as a critical contributor to erdafitinib resistance. Moreover, hypusinated eIF5A, catalyzed by SRM-mediated spermidine production, facilitated the efficient translation of HMGA2, which in turn promoted the expression of EGFR. Notably, pharmacologic inhibition of SRM enhanced the efficacy of erdafitinib both in vitro and in vivo. Together, these results offer evidence that targeting SRM could attenuate the translation of HMGA2 and subsequently reduce EGFR transcription, thus enhancing the sensitivity of FGFR-mutant bladder cancer cells to erdafitinib treatment.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3217
J Biol Chem. 2025 Mar 25. pii: S0021-9258(25)00299-6. [Epub ahead of print] 108450

Low dose Taxol causes mitochondrial dysfunction in actively respiring cancer cells.

Rozhin Penjweini, Katie A Link, Shureed Qazi, Nikhil Mattu, Adam Zuchowski, Alexandra Vasta, Dan L Sackett, Jay R Knutson.

  Mitochondrial oxygen consumption, dynamics and morphology play roles in the occurrence, development and drug resistance of cancer; thus they are main targets for many anticancer drugs. Increased mitochondrial oxygen consumption and impaired oxygen delivery creates hypoxia, which influences the balance of metabolic co-factors for biogenesis, disease progression and response to therapeutics. We therefore investigated the effects of Taxol, a well-known anticancer drug, on mitochondrial respiration (principally via a measure of oxidative phosphorylation (OXPHOS) versus glycolysis), morphology and dynamics. The concomitant effects of Taxol on mitochondrial adenosine triphosphate (ATP) and reactive oxygen species (ROS) production, mitochondrial membrane potential, radical-induced formation of carbonyl groups, mitochondrial release of cytochrome c, as well as cell cycle were investigated. Cells used in this study include: A549 (non-small cell lung epithelial cancer cell line), A549-ρ0 (mitochondrial DNA-depleted derivative of A549), and BEAS-2B (a non-cancer cell line derived from normal bronchial epithelium), as well as PC3 (prostate cancer) and HepG2 (hepatocellular carcinoma); these cell lines are known to have disparate metabolic profiles. Using a multitude of fluorescence-based measurements, we show that Taxol, even at a low dose, still adversely effects mitochondria of actively respiring (aerobic) cancer cells. We find an increase in mitochondrial ROS and cytochrome c release, suppression of ATP production and OXPHOS, fragmentation of the mitochondrial network and disruption of mitochondria-microtubule linkage. We find these changes in oxidative, but not glycolytic, cancer cells. Non-cancer cells, which are oxidative, do not show these changes.

Keywords:  Low-dose Taxol; Mitochondrial metabolism; OXPHOS; morphology and dynamics

DOI:  https://doi.org/10.1016/j.jbc.2025.108450
Pharmacol Res. 2025 Mar 22. pii: S1043-6618(25)00131-8. [Epub ahead of print]215 107706

Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement.

Mengdi Zhang, Jinliang Ji, Yuanyuan Lei, Fujian Qin, Yitong Tao, Ning Li, Jinlei Bian, Zhiyu Li, Maode Lai, Zhixia Qiu.

  Inhibiting de novo lipogenesis (DNL) in hepatocytes is a promising strategy for treating metabolic fatty liver diseases. ACLY, a key enzyme in the DNL pathway, has become a therapeutic target for non-alcoholic fatty liver disease (NAFLD). However, its inhibition shows mixed outcomes, depending on interventions and diets. Evidence suggests ACLY inhibition activates the ACSS2-mediated acetate metabolism and the subsequent DNL, though potential mechanisms and possible consequences remain unclear. This study found that targeting hepatic ACLY with AAV8-shRNA failed to improve NAFLD in mice fed a high-fat, high-fructose diet. Instead, it worsened inflammation and liver injury. ACLY inhibition conditionally upregulated DNL enzymes, but consistently activated the ACSS2-acetyl-CoA pathway and suppressed fatty acid oxidation. Further, ACLY inhibition led to polyunsaturated fatty acid accumulation, triggering mitochondrial dysfunction. The resulting ROS redirected carbon flux into acetate, activating the ACSS2-acetyl-CoA pathway, which promoted lipid biosynthesis and exacerbated mitochondrial dysfunction-a vicious cycle that fueled inflammation and liver damage. Dual inhibition of ACLY and ACSS2 broke this cycle by reducing hepatic acetyl-CoA flux, suppressing DNL, enhancing fatty acid oxidation via PPAR-α activation, and improving mitochondrial function. This combined targeting strategy reduced lipid accumulation, alleviated inflammation, and normalized aminotransferase levels, effectively reversing NAFLD progression.

Keywords:  ATP citrate lyase (ACLY); Acetyl-CoA; Acyl-coenzyme A synthetase short-chain family member 2 (ACSS2); De novo lipogenesis (DNL); Fatty acid oxidation; Non-alcoholic fatty liver disease (NAFLD)

DOI:  https://doi.org/10.1016/j.phrs.2025.107706
Nat Commun. 2025 Mar 28. 16(1): 3017

Programmed enhancement of endogenous iron-mediated lysosomal membrane permeabilization for tumor ferroptosis/pyroptosis dual-induction.

Luwen Zhu, Jiahao Hu, Xiaochuan Wu, Jucong Zhang, Xinyi Xu, Xiajie Huang, Bing Tian, Chun-Xia Zhao, Yongzhong Du, Liming Wu.

Ferroptosis and pyroptosis, as emerging regulated forms of cell death capable of overcoming apoptotic resistance, demonstrate promising potential in tumor therapy. Given that iron manipulation and reactive oxygen species elevation serve as common stimuli for both processes, inducing lysosomal membrane permeabilization (LMP) with ensuing release of lysosomal contents (including iron ions and cathepsins) is anticipated to realize dual induction of ferroptosis/pyroptosis. Herein, we report a folic acid and croconaine molecule-functionalized upconversion nanoparticle (UCNP-Cro/FA) that is able to mobilize intracellular stores of endogenous iron and spatiotemporally control the lysosome-intrinsic Fenton chemistry, thereby triggering LMP-associated cell death. The process of endogenous iron mobilization occurs through two key steps: Cro-mediated coordination of abundant Fe3+ ions within lysosomes, followed by UV-emitting upconversion core-mediated photoreduction, resulting in Fe2+ ions release. Both in vitro and in vivo experiments show that UCNP-Cro/FA + NIR treatment effectively boost LMP by endogenous iron-mediated •OH production, ultimately triggering irreversible tumor cell death via ferroptosis and Caspase-1/GSDMD-dependent pyroptosis pathways. Moreover, this process potentiates tumor immunogenicity, holding promise for tumor immunotherapy. Overall, this work proposes a feasible tumor therapy strategy that integrates ferroptosis and pyroptosis through the efficient application and activation of endogenous iron.

DOI: https://doi.org/10.1038/s41467-025-58124-7
J Transl Med. 2025 Mar 25. 23(1): 370

ZBTB6 promotes breast cancer progression by inhibiting ARHGAP6 transcription and modulating the STAT3 signaling pathway.

Xiaojiang Tang, Chaowei Deng, Yang Liu, Shengyu Pu, Qi Zheng, Yudong Zhou, Na Hao.

   BACKGROUND: The ZBTB (zinc finger and BTB domain-containing) protein family comprises a significant class of transcription factors that interact with various corepressors and histone/protein-modifying enzymes. This interaction facilitates chromatin remodeling and the regulation of gene silencing or activation, thereby playing a crucial role in cancer progression. However, the biological effects and molecular mechanisms of ZBTB6, a member of the ZBTB family, in cancer remain unclear.
METHODS: The expression levels of ZBTB6 in breast cancer (BC) were investigated through public database queries, real-time quantitative PCR (qRT‒PCR), and Western blot analysis. The effects of ZBTB6 on BC cell viability were assessed via MTT assays. Flow cytometry was utilized to analyze the cell cycle distribution and apoptosis. Additionally, cell-derived xenograft experiments were conducted to study the impact of ZBTB6 on BC growth in vivo. The relationship between ZBTB6 and the ARHGAP6 promoter was evaluated via bioinformatics predictions, chromatin immunoprecipitation (ChIP) coupled with qRT‒PCR, and luciferase reporter assays.
RESULTS: Our study demonstrated that ZBTB6 is highly expressed in primary BC specimens and cell lines and strongly correlated with tumor grade and poor prognosis. In vitro, ZBTB6 knockdown inhibited cell viability and cell cycle progression while promoting apoptosis; conversely, ZBTB6 overexpression elicited the opposite effects. In vivo, the inhibition of ZBTB6 expression in BC cells significantly suppressed tumor growth. Furthermore, we identified ARHGAP6 as a transcriptional target downstream of ZBTB6, with ZBTB6 binding to the promoter region of ARHGAP6 to repress its transcription. Notably, ARHGAP6 can exert an inhibitory effect on tumors by attenuating STAT3 activity. Our results indicate that ZBTB6 overexpression enhances the STAT3 signaling pathway, whereas ARHGAP6 overexpression counteracts the effects of ZBTB6 overexpression in BC cells.
CONCLUSION: These findings suggest that ZBTB6 promotes breast cancer progression by repressing the transcription of ARHGAP6 and activating the STAT3 signaling pathway. Consequently, ZBTB6 may serve as a potential prognostic biomarker or therapeutic target for breast cancer patients.

Keywords:  ARHGAP6; Apoptosis; Breast cancer; Cell cycle; STAT3 signaling pathway; ZBTB6

DOI:  https://doi.org/10.1186/s12967-025-06364-y
Mol Cell. 2025 Mar 19. pii: S1097-2765(25)00186-8. [Epub ahead of print]

PI3Kβ functions as a protein kinase to promote cellular protein O-GlcNAcylation and acetyl-CoA production for tumor growth.

Xuxiao He, Deyu Chen, Guijun Liu, Qingang Wu, Hong Zhao, Dong Guo, Xiaoming Jiang, Min Li, Ying Meng, Yucheng Yin, Xianglai Ye, Shudi Luo, Yan Xia, Tony Hunter, Zhimin Lu.

  Phosphatidylinositol 3-kinase (PI3K) phosphorylates PI(4,5)P2 to produce PI(3,4,5)P3, thereby activating AKT and other effector proteins. However, whether PI3K has non-PI(3,4,5)P3-related functions critical for tumor development remains unclear. Here, we demonstrate that high glucose induces PI3Kβ binding to O-linked β-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) in glioblastoma cells, dependent on hexokinase 1 (HK1)-mediated OGT Y889 phosphorylation and subsequent p85α recruitment. Importantly, PI3Kβ functions as a protein kinase, phosphorylating OGT at T985 and enhancing OGT activity and total cellular protein O-GlcNAcylation. Activated OGT O-GlcNAcylates ATP-citrate synthase (ACLY) at T639 and S667, leading to ACLY activation-dependent acetyl-coenzyme A (CoA) production to increase fatty acid levels and histone H3 acetylation for gene transcription. Intervention in PI3Kβ-mediated OGT phosphorylation and ACLY O-GlcNAcylation inhibits glioblastoma cell proliferation and tumor growth in xenografts. These findings underscore the critical role of PI3Kβ in governing protein O-GlcNAcylation, fatty acid metabolism, and chromatin modification through its protein kinase activity and provide instrumental insight into the roles of PI3K in tumor progression.

Keywords:  ACLY; HK1; OGT; PI3K; acetyl-CoA; fatty acid production; histone; tumor

DOI:  https://doi.org/10.1016/j.molcel.2025.02.024
Digestion. 2025 Mar 27. 1-19

KIF4A facilitates oxaliplatin resistance and stemness in colon cancer by boosting glucose metabolism.

Cheng Cai, Xia Zhang, Chenyang Ge, Shicheng Zhou, Zhekang Jin, Kangfu Dai, Nannan Dai, Xingxing Yu, Jianping Wang.

BACKGROUND: Colon cancer (CC) is a malignant tumor commonly found in the intestines with high incidence and mortality rates. Oxaliplatin (OXA) is a platinum-based chemotherapy drug widely used to treat CC. However, frequent drug resistance in patients results in suboptimal treatment outcomes. Though kinesin family member 4A (KIF4A) has been reported to be upregulated in various cancers and linked with poor prognosis in patients, its regulatory mechanism in cellular metabolism remains unclear.
METHODS: The Human CC/OXA-resistant cell line (HCT116-R) was constructed. CCK-8 assay was employed to calculate the half-maximal inhibitory concentration (IC50) of CC cells. The level of cell stemness was assessed by cell sphere formation assay. The enrichment of KIF4A in signaling pathways of CC was analyzed through gene set enrichment analysis (GSEA). The bioinformatics analysis was applied to reveal the differential expression of KIF4A in CC and its correlation with genes related to stemness or glycolysis. The assessment of lactate in the supernatant was finished by utilizing the lactate detection kit. The oxidative phosphorylation and glycolysis levels in cells were measured by a Seahorse analyzer. The mRNA expression level of KIF4A was detected by quantitative real-time PCR. Furthermore, the western blot (WB) was employed to determine the protein expression of glycolysis-related enzymes in cells. A mouse OXA-resistant CC xenograft tumor model was established, with changes in tumor volume and final weight recorded. TUNEL was utilized to detect the apoptosis level in tissues and immunohistochemistry (IHC) to examine the distribution of KIF4A and ki-67 in tissues. The levels of stemness-related proteins in tissues were detected through WB.
RESULTS: KIF4A was upregulated in CC, exhibiting a positive association with OXA resistance. High expression of KIF4A promoted cancer cell survival and cancer stemness. In GSEA prediction, KIF4A in CC may be linked with the glycolysis pathway. Correspondingly, the expression of KIF4A in CC was positively correlated with the expression of glycolysis-related proteins. Tests for lactate content and glycolysis/oxidative phosphorylation levels revealed that knocking down KIF4A repressed glycolytic function in the drug-resistant strain but reinforced mitochondrial oxidative phosphorylation. Furthermore, KIF4A overexpression effectively boosted the OXA resistance and stemness of cells, which was reversed by glycolysis inhibitor. The mouse model validated the above results.
CONCLUSION: KIF4A is significantly upregulated in CC to reinforce the glycolysis of cancer cells, thus facilitating cell stemness and resistance to OXA-based therapy.

DOI: https://doi.org/10.1159/000544914
Cell Rep. 2025 Mar 24. pii: S2211-1247(25)00205-0. [Epub ahead of print]44(4): 115434

SOD2 is a regulator of proteasomal degradation promoting an adaptive cellular starvation response.

Nurul Khalida Ibrahim, Sabine Schreek, Buesra Cinar, Anna Sophie Stasche, Su Hyun Lee, Andre Zeug, Tim Dolgner, Julia Niessen, Evgeni Ponimaskin, Halyna Shcherbata, Beate Fehlhaber, Jean-Pierre Bourquin, Beat Bornhauser, Martin Stanulla, Andreas Pich, Alejandro Gutierrez, Laura Hinze.

  Adaptation to changes in amino acid availability is crucial for cellular homeostasis, which requires an intricate orchestration of involved pathways. Some cancer cells can maintain cellular fitness upon amino acid shortage, which has a poorly understood mechanistic basis. Leveraging a genome-wide CRISPR-Cas9 screen, we find that superoxide dismutase 2 (SOD2) has a previously unrecognized dismutase-independent function. We demonstrate that SOD2 regulates global proteasomal protein degradation and promotes cell survival under conditions of metabolic stress in malignant cells through the E3 ubiquitin ligases UBR1 and UBR2. Consequently, inhibition of SOD2-mediated protein degradation highly sensitizes different cancer entities, including patient-derived xenografts, to amino acid depletion, highlighting the pathophysiological relevance of our findings. Our study reveals that SOD2 is a regulator of proteasomal protein breakdown upon starvation, which serves as an independent catabolic source of amino acids, a mechanism co-opted by cancer cells to maintain cellular fitness.

Keywords:  CP: Cancer; CP: Molecular biology; SOD2; UBR1; UBR2; amino acid starvation; cancer; drug resistance; leukemia; protein degradation

DOI:  https://doi.org/10.1016/j.celrep.2025.115434
Mol Med. 2025 Mar 25. 31(1): 115

Knockdown of SLC7A5 inhibits malignant progression and attenuates oxaliplatin resistance in gastric cancer by suppressing glycolysis.

Yan Zhang, Jian Cao, Zheng Yuan, Jiahui Zhou, Hao Zuo, Xinsheng Miao, Xinhua Gu.

   BACKGROUND: Chemotherapy resistance is a major challenge in the treatment of intermediate and advanced gastric cancer (GC). This study aimed to recognize oxaliplatin resistance-related genes (OXARGs) in GC and to explore their role and mechanism in oxaliplatin resistance of GC.
METHODS: OXARGs with prognostic value in GC were analyzed using GC oxaliplatin resistance data from the GEO and TCGA databases. RT-qPCR and WB assay were applied to verify the expression of MT2A, NOTCH1 and SLC7A5 in oxaliplatin-resistant GC cells (HGC27R and MKN45R). The effect of SLC7A5 on the malignant phenotype of oxaliplatin-resistant GC cells was verified by CCK-8, EDU, TUNEL, colony formation, wound healing, transwell assay, tumor bearing experiments and WB assay.
RESULTS: Bioinformatics analysis and experimental validation indicate that SLC7A5 was a target for oxaliplatin-resistance in GC. Knockdown of SLC7A5 obviously decreased the viability, migration, and invasion of oxaliplatin-resistant GC cells in vitro and tumor growth in vivo. It also increased the apoptosis levels and BAX expression, and reduced the expression of BCL2, MMP 2 and MMP9. Additionally, the knockdown of SLC7A5 enhanced the sensitivity of oxaliplatin-resistant GC cells to oxaliplatin both in vitro and in vivo. Furthermore, knockdown of SLC7A5 downregulated the expression of HK2, LDHA, Glut1, and PDK1 both in vivo and in vitro, leading to increased extracellular glucose levels and decreased lactate levels. However, glutathione significantly attenuated the regulatory effect of SLC7A5 knockdown on the malignant phenotype of oxaliplatin-resistant GC cells.
TRIAL REGISTRATION: Not Applicable.
CONCLUSION: Knockdown of SLC7A5 inhibits malignant progression and attenuates oxaliplatin resistance in GC by suppressing glycolysis.

Keywords:  Bioinformatics; Gastric cancer; Glycolysis; Oxaliplatin resistance; SLC7A5

DOI:  https://doi.org/10.1186/s10020-025-01175-9