bims-prolim 2025-09-07 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–09–07
twenty papers selected by
Bruna Martins Garcia, CABIMER

Lactylation in Cancer: Advances, Challenges, and Future Perspectives.
Pharmacological Targeting of DHHC9-Mediated STRN4 Palmitoylation to Suppress YAP-Driven Cancer Metastasis.
Effects of lactylation on the hallmarks of cancer (Review).
Lactylation modification in lung cancer: A review of current research and future directions (Review).
Design of a selective peptide inhibitor targeting KDM5C demethylase activity.
The lactylation of glucose-6-phosphate dehydrogenase promotes malignant phenotypes in cancer cell lines.
Hypoxia-Induced PRMT1 Lactylation Drives Vimentin Arginine Asymmetric Dimethylation in Tumor Metastasis.
Recent advances in S-palmitoylation and its emerging roles in human diseases.
CAFs promote immune evasion in gastric cancer through histone lactylation-mediated suppression of NCAPG ubiquitination.
Altered protein lipidation in cancer: A hidden link to sensory neuronal dysfunction.
Profiling Protein Post-Translational Modifications in Plasma-derived Extracellular Vesicles as Fingerprints for Breast Cancer Subtypes.
Construction of lactylation (LA) risk signature in prostate cancer based on 4D fast DIA L-lactated quantitative genomics.
ATE1 promotes breast cancer progression via arginylation-dependent regulation of MAPK-MYC signaling.
Palmitoylation-dependent modulation of CD36 trafficking and signaling integrates lipid uptake with metabolic disease pathogenesis.
The tRNA editing complex ADAT2/3 promotes cancer cell growth and codon-biased mRNA translation.
A plasma metabolite-based test to detect minimal residual disease in post-surgery patients with colorectal cancer.
β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD+/NADH balance and mitochondrial acetylation.
Engineering protein prenylation: an emerging tool for selective protein modification.
C-mannosylation promotes ADAMTS1 activation and secretion in human testicular germ cell tumor NEC8 cells.
N(6)-methyladenosine modification of ADGRA3 by ZC3H13 suppresses papillary thyroid cancer cell malignancy by inactivating the PI3K/Akt/mTOR signaling pathway.

Cancer Res. 2025 Sep 02. 85(17): 3192-3195

Lactylation in Cancer: Advances, Challenges, and Future Perspectives.

Zhi Zong, Long Zhang, Fangfang Zhou.

Since its discovery in 2019, lactylation has emerged as a critical posttranslational modification with significant implications for cancer biology. Lactylation involves lactyltransferase-mediated addition of lactate to lysine residues on both histone and nonhistone proteins. In this study, we summarize key advances in research on lactylation and cancer. Lactylation functions in tumor progression and represents a therapeutic target and biomarker. The field currently faces many challenges, such as identifying specific "readers" of lactylation and developing precise tools for studying its biological impact. This perspective aims to provide insights into the role of lactylation in cancer and to stimulate further exploration.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4394
J Cell Mol Med. 2025 Sep;29(17): e70815

Pharmacological Targeting of DHHC9-Mediated STRN4 Palmitoylation to Suppress YAP-Driven Cancer Metastasis.

Yang Tian, Wei Li, Qing Zhai, Ying Yu, Jiaxin Yuan, Yan Ma, Jingjing Yang, Mingyue Li, Wenwen Chang, Wenjing Li, Keke Huang, Chongran Sun, Chen Zeng, Yingdi Sun, Jiabao Gu, Huilin Zhang, Dameng Li, Yanan Yu, Lu Hu, Peng Zhang, Bo Ma, Junnian Zheng, Pan Li, Feng Guo, Yang Sun.

  Protein S-palmitoylation, a dynamic and reversible post-translational modification involving the attachment of palmitate to cysteine residues, is a key regulator of protein functionality and cellular signalling. Dysregulation of this modification has emerged as a critical driver of cancer progression. Among the 23 DHHC palmitoyl transferases responsible for catalysing S-palmitoylation, aberrant expression of specific members is linked to tumorigenesis and development, underscoring their potential as promising therapeutic targets. However, the cancer-specific roles and substrates of individual DHHC enzymes remain poorly characterised. In this study, we identified DHHC9 as a crucial regulator of adenocarcinoma progression, including colorectal and lung cancers. Functional studies demonstrated that DHHC9 knockdown profoundly inhibited cell migration in vitro and tumour metastasis in vivo. Proteomic and functional analyses revealed that STRN4, a core component of the STRIPAK complex, was palmitoylated by DHHC9 at cysteine 701. The STRN4 palmitoylation reduced YAP phosphorylation, promoted nuclear translocation of YAP and activated downstream Hippo pathway transcriptional targets-including CCN1, CCN2 and ANKRD1-thereby driving cancer cell migration. Notably, we discovered two small molecules, Treprostinil and 10-HCPT, as potent DHHC9 inhibitors that effectively suppressed adenocarcinoma cell migration. Our findings define the DHHC9-STRN4-YAP axis as a novel mechanism linking palmitoylation to phosphatase regulation and Hippo pathway dysregulation, unveiling DHHC9 as a highly promising therapeutic target in cancer treatment.

Keywords:  STRN4 palmitoylation; ZDHHC9; adenocarcinoma metastasis; hippo pathway; palmitoylation inhibitors

DOI:  https://doi.org/10.1111/jcmm.70815
Oncol Lett. 2025 Nov;30(5): 492

Effects of lactylation on the hallmarks of cancer (Review).

Yujie Fan, Zhangda Chen, Jiaxin Li, Lidan Ding.

  Lactylation, an emerging metabolism-dependent post-translational modification, serves as a core mechanism linking metabolic reprogramming with epigenetic regulation in establishing the multifaceted hallmarks of cancer. The present review systematically elucidates how lactylation dynamically regulates the functions of both histone and non-histone proteins, driving the acquisition of classical cancer hallmarks including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, induction of angiogenesis, activation of invasion and metastasis and replicative immortality. Furthermore, lactylation is intricately involved in enabling the emerging hallmarks of cancer, such as the maintenance of genome instability, shaping of a pro-inflammatory tumor microenvironment (TME), immune escape, metabolic reprogramming, unlocking phenotypic plasticity and non-mutational epigenetic reprogramming. By reshaping the interaction networks among cancer, stromal and immune cells within the TME, lactylation promotes the formation of an immunosuppressive microenvironment and enhances resistance to therapy. Targeting lactylation regulatory pathways (such as lactate dehydrogenase A inhibitors, monocarboxylate transporter inhibitors and delactylase activators) can reverse key hallmark phenotypes, highlighting novel therapeutic avenues for the development of precision anticancer strategies based on interrupting metabolic-epigenetic crosstalk.

Keywords:  cancer; hallmark; lactate; lactylation; microenvironment; post-translational modification

DOI:  https://doi.org/10.3892/ol.2025.15238
Oncol Rep. 2025 Nov;pii: 148. [Epub ahead of print]54(5):

Lactylation modification in lung cancer: A review of current research and future directions (Review).

Qingguo Lv, Jianan Xu, Na Hu, Yujun Zhao, Xin Wang, Tan Wang, Lin Tian.

  Lung cancer is a common malignancy that poses risks to human health and quality of life. The primary treatment options currently available include surgery, chemotherapy and radiotherapy. However, the aggressive metastatic nature of the disease combined with the development of drug and radiation resistance results in suboptimal survival outcomes. Consequently, there is a need to explore novel therapeutic approaches and develop more effective drugs. Lactylation, an epigenetic modification induced by lactate, alters histone proteins to modify the chromatin structure, as well as non‑histone proteins. This post‑translational modification is associated with the initiation and progression of lung cancer. Lactylation carries out a considerable role in the onset, progression and resistance of the disease by influencing tumor metabolism and the surrounding microenvironment. Targeting lactylation could provide innovative strategies for the targeted therapy of lung cancer.

Keywords:  Warburg effect; epigenetics; lactylation; lung cancer; therapy strategies

DOI:  https://doi.org/10.3892/or.2025.8981
Structure. 2025 Aug 20. pii: S0969-2126(25)00303-X. [Epub ahead of print]

Design of a selective peptide inhibitor targeting KDM5C demethylase activity.

Valentina Lukinović, Hemanta Adhikary, Matthew Hoekstra, Ali Shukri, Francois Charih, Anand Chopra, Kyle K Biggar.

  Post-translational modifications, particularly protein lysine demethylation, intricately regulate diverse cellular processes. Dysregulation of this modification often precipitates human pathologies by perturbing substrate protein functions, stability, and interactions. Lysine demethylases (KDMs), such as the KDM5 family, are crucial in removing methyl marks. In particular, KDM5C has gained prominence for its role in cancer biology and drug resistance. These enzymes, specializing in erasing lysine methylation marks-especially from histone H3 lysine 4 (H3K4)-directly influence gene transcription. This study pioneers the design of a peptide inhibitor of KDM5C demethylase activity. This novel inhibitor displays remarkable selectivity for KDM5C over other family members. Intriguingly, in vivo experiments demonstrate that this inhibitor significantly reduces tumor growth. These findings highlight the potential of targeting KDM5C inhibition as a strategy for colon cancer treatment. Moreover, these findings underscore the promise of peptide inhibitors as targeted therapies, emphasizing their potential in altering the trajectory of cancer therapeutics.

Keywords:  RNF20 methylation; histone H3K4me3; lysine demethylation; peptide arrays; peptide inhibitor; post-translational modification; therapeutics; xenograft model

DOI:  https://doi.org/10.1016/j.str.2025.08.001
Mol Biol Rep. 2025 Sep 03. 52(1): 861

The lactylation of glucose-6-phosphate dehydrogenase promotes malignant phenotypes in cancer cell lines.

Yan Zhang, Ying Wu, Aoxing Cheng, Fengjuan Cui, Zhenye Yang, Jing Guo.

   BACKGROUND: Malignant tumors are characterized by their reliance on hyperactive glycolysis (Warburg effect), marked by increased glucose uptake, lactate secretion, and preferential glucose flux into glycolysis and the pentose phosphate pathway (PPP). These metabolic shifts provide energy, biosynthetic precursors, and maintain redox balance, supporting tumor proliferation. However, the regulatory crosstalk between glycolysis and PPP remains poorly understood. This study investigates how tumors coordinate these pathways to drive progression via metabolic reprogramming.
METHODS AND RESULTS: Exogenous lactate supplementation in A549 cells increased the NADPH/NADP+ ratio, enhanced fatty acid synthesis, and upregulated the PPP. Western blotting revealed lactylation of glucose-6-phosphate dehydrogenase (G6PD), which correlated with intracellular lactate levels, modulated by rotenone treatment or lactate dehydrogenase A (LDHA) overexpression. LDHA knockdown significantly reduced G6PD lactylation. Enzyme assays confirmed that lactylation enhanced G6PD activity. Through truncation and mutagenesis analyses, we identified lysines 45-47 as the key lactylation site, which enhances NADP⁺ binding and promotes G6PD dimerization. Mutation of this site impaired cancer cell proliferation and migration in vitro and suppressed tumor growth in vivo. Mechanistically, G6PD lactylation serves as a metabolic switch, linking PPP activation to oncogenic progression.
CONCLUSIONS: Lactate drives tumor progression through G6PD lactylation, activating the PPP and facilitating glycolysis-PPP crosstalk. This study uncovers a novel metabolic rewiring mechanism that promotes oncogenic synergy.

Keywords:  Cancer; Glucose-6-phosphate dehydrogenase; Lactylation; Pentose phosphate pathway

DOI:  https://doi.org/10.1007/s11033-025-10960-y
Adv Sci (Weinh). 2025 Aug 30. e09861

Hypoxia-Induced PRMT1 Lactylation Drives Vimentin Arginine Asymmetric Dimethylation in Tumor Metastasis.

Jia Zhou, Shuying Qiu, Xia Yang, Yan Wu, Xinxia Yao, Hangqi Hu, Jingfeng Luo, Chandra Sugiarto Wijaya, Lingfeng Ma, Xiaojun Long, Lingna Xu, Jinquan Liu, Chaoqun Wang, Yibin Pan, Xiaona Chen, Hongchuan Jin, Xian Wang.

  Metastasis contributes to around 90% of cancer mortality, but effective strategies to disrupt metastatic cascades remain elusive. Hypoxia-driven epithelial-mesenchymal transition (EMT) promotes cancer cell spread, yet the post-translational mechanisms governing cytoskeletal reprogramming here remain incompletely defined. This study reports a hypoxia-inducible post-translational modification cascade: under hypoxia, protein arginine methyltransferase 1 (PRMT1) is lactylated at evolutionarily conserved residues K134/K145, enhancing its methyltransferase activity to catalyze the asymmetric dimethylation (aDMA) of vimentin at R64. This modification drives vimentin filament assembly, cytoskeletal remodeling, and metastasis in preclinical models. shPRMT1 or vimentin R64K mutation (methylation-deficient) abrogates hypoxia-enhanced migration in vitro and metastasis in vivo. Hypoxia reduces the protein levels of HDAC8 (PRMT1's delactylase), boosting PRMT1 lactylation. PRMT1 K134R/K145R mutants (lactylation - deficient) lose the ability to bind vimentin and fail to rescue filament formation. In triple-negative breast cancer (TNBC), vimentin R64 aDMA levels correlate with advanced tumor stage and poor patient survival. PRMT1 inhibitor MS023 reduces xenograft metastasis with low toxicity. These findings establish a hypoxia-PRMT1-vimentin axis, identifying vimentin R64 aDMA as a metastatic regulator. Inhibiting PRMT1 represents a promising anti-metastasis strategy.

Keywords:  PRMT1; arginine methylation; cancer metastasis; hypoxia; lactylation; vimentin

DOI:  https://doi.org/10.1002/advs.202509861
J Hematol Oncol. 2025 Sep 01. 18(1): 83

Recent advances in S-palmitoylation and its emerging roles in human diseases.

Juanjuan Shang, Mei Ding, Xiangxiang Zhou.



Keywords:  APTs; Cancers; Post-translational modification; S-palmitoylation; ZDHHCs

DOI:  https://doi.org/10.1186/s13045-025-01738-7
J Transl Med. 2025 Sep 02. 23(1): 989

CAFs promote immune evasion in gastric cancer through histone lactylation-mediated suppression of NCAPG ubiquitination.

Sheng Zhou, Linmei Xiao, Li Hu, Fei Zuo, Yuanhang Wang, Bojian Fei, Jialin Dai, Xinyi Zhou.

   BACKGROUND: Cancer-associated fibroblasts (CAFs) can facilitate tumor progression through multiple approaches. Research indicates that CAFs in various tumors exhibit robust lactate metabolism, ultimately becoming the primary source of lactate in the tumor microenvironment. Emerging evidence has established that CAFs could orchestrate gastric cancer (GC) immune evasion. However, the potential role of CAFs-derived lactate in immunotherapy remains elusive.
METHODS: In our research, CUT&Tag and transcriptome sequencing were employed to detect the target gene of histone lactylation. Co-immunoprecipitation, mass spectrometry analysis, and molecular docking, were utilized to explore the interactions between proteins. We performed cellular, animal, and organoid experiments to verify the mechanism.
RESULTS: We found that lactate secreted by CAFs was elevated, facilitating the lactylation of H3K18 in GC cells. As a target of H3K18la, ASPM played crucial roles in regulating the GC progression by promoting resistance to anti-PD-1. Mechanistically, ASPM promoted the transport of NCAPG from the nucleus to the cytoplasm by directly binding to it and then enhanced the deubiquitination of NCAPG mediated by BUB3, thereby increasing the expression of NCAPG. Furthermore, NCAPG targeted the SRC/STAT3 pathway and elevated PD-L1 expression. In addition, Daturilin has been preliminarily identified as a small-molecule inhibitor targeting NCAPG.
CONCLUSIONS: In conclusion, we have identified that CAFs-derived lactate promoted GC progression and clarified its mechanism, proposing the H3K18la-ASPM-NCAPG axis. Daturilin could enhance the therapeutic efficacy of anti-PD-1 treatment. This offers innovative perspectives on the complex role of CAFs in the TME and the influence of lactate on tumor progression.

Keywords:  Cancer-associated fibroblasts; Gastric cancer; Lactate; Ubiquitination

DOI:  https://doi.org/10.1186/s12967-025-07013-0
Comput Biol Chem. 2025 Aug 25. pii: S1476-9271(25)00317-2. [Epub ahead of print]120(Pt 1): 108656

Altered protein lipidation in cancer: A hidden link to sensory neuronal dysfunction.

Iman H Ibrahim, Ahmed Abdellatif, Heba A Eassa.

  Protein lipidation/delipidation affects protein functions, interactions, and membrane trafficking. Dysregulation of this process might lead to tissue disorganization, abnormal proliferation, migration, and poor prognosis in cancer. While dysregulation of lipidation/delipidation in neurons has been associated with several neurodegenerative diseases, its potential link to neuronal dysfunction in cancer patients remains unexplored. The aim of the study is to explore the association of altered protein lipidation with neurological problems in cancer patients via bioinformatic analysis. Gene list related to protein lipidation was retrieved and the effect of gene set alteration on overall survival on cancer patients was inquired using public dataset of cancer. Differentially expressed genes were analyzed for susceptibility to protein lipidation, distribution on chromosomes, Gene Ontology, and pathway enrichment analysis. Further enrichment and transcription factor targets analyses were performed. Differentially expressed genes (DEGs) in cancer patients with altered protein lipidation/delipidation were found to be associated with enrichment of neuronal regeneration/degeneration pathways, olfactory receptor signaling, and sensory perception pathways. Specifically, targets of Translational elongation factor EF-1 (TEF1) and signal transducer and activator of transcription 1 (STAT1) were enriched in the DEGs of patients with altered protein lipidation. Both TEF1 and STAT1 require lipidation for proper functioning. Therefore, altered lipidation in cancer patients could be associated with the disturbance of their downstream targets. These targets are significantly correlated to multiple pathways and processes related to neurological, sensory, and motor functions.

Keywords:  Cancer; Differentially expressed genes; Palmitoylation; Protein delipidation; Protein lipidation; Sensory perception

DOI:  https://doi.org/10.1016/j.compbiolchem.2025.108656
Res Sq. 2025 Aug 21. pii: rs.3.rs-7294729. [Epub ahead of print]

Profiling Protein Post-Translational Modifications in Plasma-derived Extracellular Vesicles as Fingerprints for Breast Cancer Subtypes.

Marco Hadisurya, Hillary Andaluz Aguilar, I-Hsuan Chen, Mengting Xu, J Sebastian Paez, Rachit Bisht, Jyoti Singh, Zheng-Chi Lee, Amirhesam Mashaollahi, Anton B Iliuk, Weizhou Zhang, W Andy Tao.

Addressing tumor heterogeneity in breast cancer (BC) research is crucial, given the distinct subtypes like triple-negative (TN), luminal A/B (LAB), and HER2, requiring precise differentiation for effective treatment. This study introduces a non-invasive method by analyzing post-translationally modified proteins in plasma extracellular vesicles (EVs), which play a role in immune regulation and intercellular communication. Examining modifications like phosphorylation, acetylation and glycosylation in EVs provides insights into BC dynamics. One hundred and one plasma samples from LAB BC, TN BC and healthy individuals underwent discovery and validation experiments. The study identified over 28,000 unique non-modified peptides, 5,000 phosphopeptides, 680 acetyl peptides and 1,300 glycopeptides that were successfully characterized. Bioinformatics analyses revealed significant overexpression of 815 non-modified proteins, 3,958 phosphopeptides, 352 acetyl peptides and 895 glycopeptides in LAB BC or TN BC subtypes. Phosphorylated and glycosylated PD-L1 peptides emerged as potential markers for BC, regardless of subtype. Aligning the findings with literature and PAM50 gene signatures highlighted markers correlated with lower survival rates. The study also conducted 123 scheduled parallel reaction monitoring (PRM) analyses, leveraging machine learning to pinpoint a panel of specific modification sites with high accuracy for subtype differentiation. This research reveals diagnostic markers and enhances understanding of the molecular landscape, contributing to more effective and personalized BC diagnostics and treatments.

DOI: https://doi.org/10.21203/rs.3.rs-7294729/v1
J Transl Med. 2025 Aug 28. 23(1): 967

Construction of lactylation (LA) risk signature in prostate cancer based on 4D fast DIA L-lactated quantitative genomics.

Fan Zou, Yongchen Jin, Ziteng Zhang, Yishan Zhang, Mingdong Wang, Fangge Zhu, Jinming Qiu, Haoyuan Ye, Yi Fu, Hao Ping.

   BACKGROUND: Lactylation (LA) plays a crucial role in regulating protein stability, angiogenesis, and immune modulation. Global lactylation of proteins in prostate cancer cells is a key event in tumor progression. This study aimed to explore the characteristics of LA in patients with prostate cancer (PRAD) and construct a LA-related risk model to predict prognosis.
METHODS: LA-related genes in prostate cancer were screened through quantitative lactylation proteomics of human tissues from Beijing Tongren Hospital, Capital Medical University. Based on the TCGA and GEO databases, patients were divided into two LA-related gene clusters. Principal component analysis (PCA) was used to identify the heterogeneity of the grouping, and differentially expressed genes (DEGs) between the clusters were identified. A LA risk model was constructed using Lasso-Cox regression analysis, and its efficacy was verified in the TCGA, GSE116918, and GSE70769 cohorts through K-M curves, receiver operating characteristic (ROC) curves, and nomograms. The most representative gene, KCNMA1, was selected for in vitro and animal experiments to verify its association with prostate cancer.
RESULTS: Based on quantitative lactylation proteomics, two LA clusters were identified in prostate cancer and were significantly associated with prognosis. A total of 122 DEGs were screened to construct a gene risk model. The K-M curves verified the differences between the high - and low - risk groups of the model in the test group and the training cohort (test group: P = 0.025; training group: P < 0.001). The ROC curve verified that the prognostic model had good accuracy. The nomogram integrating staging and LA risk factors showed high accuracy and reliability in predicting the prognosis of prostate cancer. The expression of KCNMA1 in PCa was significantly lower than that in NATs, and its expression level decreased with the increase in grading. In cell experiments, overexpression of KCNMA1 promoted the infiltration of M1 macrophages by inhibiting the RAS/RAF/MEK/ERK signaling pathway, thereby inhibiting the proliferation, migration, and invasion of prostate cancer cells. Animal experiments demonstrated that overexpression of KCNMA1 inhibited the growth rate of tumors.
CONCLUSION: The LA risk model constructed in this study can effectively predict the prognosis of prostate cancer and is expected to become a new type of test scoring criterion. KCNMA1 is expected to become a novel target for prostate cancer.

Keywords:  Bioinformatics; KCNMA1; Lactylation; MAPK signaling pathway; Prognostic model

DOI:  https://doi.org/10.1186/s12967-025-06990-6
Cell Commun Signal. 2025 Sep 02. 23(1): 390

ATE1 promotes breast cancer progression via arginylation-dependent regulation of MAPK-MYC signaling.

Laxman Nawale, Shinyeong Ju, Jung Gi Kim, Nak Kyun Soung, Bo Yeon Kim, Cheolju Lee, Hyunjoo Cha-Molstad.

   BACKGROUND: Arginyl-tRNA-protein transferase (ATE1) catalyzes N-terminal arginylation, a regulatory protein modification implicated in various cellular processes, including proliferation, apoptosis, and migration. Although ATE1 has context-dependent roles in cancer, its specific function in breast cancer remains unclear. This study investigates the oncogenic role of ATE1 across multiple breast cancer subtypes and its underlying molecular mechanisms.
METHODS: ATE1 expression in breast cancer was evaluated using TCGA data and immunoblotting across breast cancer cell lines and normal mammary epithelial cells (HMEC). Functional studies using siRNA- and shRNA-mediated knockdown assessed ATE1's role in cell viability, clonogenic growth, migration, and tumorigenesis in vitro and xenograft models. Quantitative proteomics, R-catcher-based N-terminomics, and pathway analyses were employed to identify ATE1-dependent signaling networks, with a focus on MAPK-MYC axis regulation. Flow cytometry and immunoblotting were used to assess cell cycle progression, apoptosis, and MYC stability.
RESULTS: ATE1 was significantly upregulated in breast cancer cells and associated with poor prognosis in early-stage patients. ATE1 depletion selectively impaired viability, proliferation, and migration in breast cancer cells, but not in HMECs. In vivo, ATE1 silencing suppressed tumor growth in xenograft models. Proteomic profiling revealed that ATE1 regulates the cell cycle and survival pathways in a subtype-specific manner, particularly through modulation of the MAPK-MYC-CDK6 axis in luminal T-47D cells. ATE1 stabilized MYC protein via ERK-mediated phosphorylation at Ser62, promoting cell cycle progression and suppressing apoptosis. Rescue experiments confirmed that ATE1's tumor-promoting activity depends on its arginyltransferase function.
CONCLUSIONS: ATE1 promotes breast cancer progression by enhancing cell proliferation, survival, and migration through MAPK-dependent stabilization of MYC in a lineage-specific context. These findings identify ATE1 as a potential therapeutic target and highlight the relevance of protein arginylation in the molecular heterogeneity of breast cancer.

Keywords:  ATE1 (arginyltransferase 1); Breast cancer; Cell proliferation; Cell survival; MYC signaling; N-degron pathway; N-terminal arginylation; Tumor progression

DOI:  https://doi.org/10.1186/s12964-025-02376-9
Pharmacol Res. 2025 Aug 28. pii: S1043-6618(25)00360-3. [Epub ahead of print] 107935

Palmitoylation-dependent modulation of CD36 trafficking and signaling integrates lipid uptake with metabolic disease pathogenesis.

Mingxun Li, Haoran Jia, Lei Zhang, Peng Chen, Shimeng Wang, Yongjiang Mao, Zhangping Yang.

  CD36 is a multifunctional lipid transporter that facilitates long-chain fatty acid uptake and orchestrates metabolic signaling in energy-demanding tissues. Recent studies have uncovered site-specific palmitoylation as a crucial post-translational modification that governs CD36 subcellular trafficking, stabilizing its localization within lipid rafts and regulating its endocytic recycling between the plasma membrane, endosomes, and lipid droplets. This dynamic palmitoylation-depalmitoylation cycle enables CD36 to spatially and temporally couple lipid transport with signal transduction in response to nutritional and hormonal cues. Disruption of this regulatory axis leads to aberrant fatty acid uptake, inflammatory activation, and metabolic dysfunction, contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), and atherosclerosis. Here, we delineate the mechanistic basis of CD36 palmitoylation-dependent trafficking and its integration with lipid handling, signal transduction, and disease pathogenesis. Targeting this regulatory interface offers a promising avenue for therapeutic intervention in metabolic disorders.

Keywords:  CD36; Fatty acid transport; Lipid metabolism; Metabolic diseases; Palmitoylation; Subcellular trafficking

DOI:  https://doi.org/10.1016/j.phrs.2025.107935
J Mol Biol. 2025 Sep 02. pii: S0022-2836(25)00480-2. [Epub ahead of print] 169414

The tRNA editing complex ADAT2/3 promotes cancer cell growth and codon-biased mRNA translation.

Julia Ramirez-Moya, Titi Rindi Antika, Qi Liu, Xushen Xiong, Raja Ali, Alejandro Gutierrez, Richard I Gregory.

  Transfer RNAs (tRNAs) are subject to various chemical modifications that influence their stability or function. Adenosine to Inosine (A-to-I) editing in the tRNA anticodon at position A34 is an important modification that expands anticodon-codon recognition at the wobble position and is required for normal mRNA translation. The relevance of tRNA editing in cancer remains unexplored. Here we show that the genes encoding the ADAT2/3 deaminase complex, responsible for A-to-I tRNA editing in humans, are commonly amplified and/or overexpressed in several tumor types including liposarcoma (LPS). We find that LPS cell growth and tumorigenicity is dependent on ADAT2/3 tRNA editing activity. Mechanistically, we find decreased tRNA editing upon ADAT2 depletion, defective translation of a subset of mRNAs, and altered protein homeostasis. Thus, ADAT2 promotes oncogenesis and the translation of growth promoting mRNAs that are enriched in NNC codons that lack cognate tRNAs and therefore depend on A-I tRNA editing for decoding and mRNA translation. Our results identify ADAT2/3 as a potential new cancer therapeutic target.

Keywords:  ADAT2; ADAT3; Editing; Inosine; cancer; epitranscriptome; mRNA translation; tRNA

DOI:  https://doi.org/10.1016/j.jmb.2025.169414
iScience. 2025 Sep 19. 28(9): 113138

A plasma metabolite-based test to detect minimal residual disease in post-surgery patients with colorectal cancer.

Zhengran Zhou, Richard Mortensen, Peishan Hu, Bo Jin, Xiao-Bin Zheng, Xiao Li, James Schilling, C James Chou, Karl G Sylvester, Yanghai Cong, Xiaojian Wu, Feng Gao, Xuefeng B Ling, Xuanhui Liu.

  Colorectal cancer (CRC) is among the leading causes of cancer-related deaths worldwide, predominantly caused by recurrence, underscoring the need for novel biomarkers for the early detection of relapse. We hypothesize that patients' response to cancer is closely linked to metabolic changes and can be detected in blood as an indicator for recurrence. Full metabolomics analysis was performed on the longitudinal samples collected from 160 patients with CRC before and after surgery for 24 months or more. Key blood metabolic biomarkers that distinguish relapse and non-relapse patients were identified, and a minimal residual disease (MRD) detection machine-learning model was constructed based on the discovered signatures. The model diagnosed CRC relapse with a sensitivity of 62% and specificity of 80%, with median and maximum lead times of 471 and 1056 days before diagnosed clinical relapse, suggesting it could be used as a novel diagnostic tool for the earlier detection of cancer relapse.

Keywords:  Machine learning; Metabolomics; Oncology

DOI:  https://doi.org/10.1016/j.isci.2025.113138
J Biol Chem. 2025 Aug 28. pii: S0021-9258(25)02488-3. [Epub ahead of print] 110636

β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD+/NADH balance and mitochondrial acetylation.

Xiujuan Wei, Chengkai Zhang, Xiaoguang Zheng, Kexin Pan, Xiaojun Ren, Xiaoting Lou, Zhengquan Yang, Ting Fu, Hezhi Fang, Jianxin Lu.

  Ketone bodies are a key alternative energy source during carbohydrate deficiency. In addition to their metabolic function, they regulate essential cellular processes, including metabolism, signal transduction, and protein post-translational modifications (PTMs). However, the role of ketone body metabolism in tumorigenesis remains poorly understood. Here, we demonstrate that ketone body synthesis metabolism is activated in pancreatic cancer, while exogenous ketone supplementation does not affect PDAC cell proliferation. Moreover, we observe a significant upregulation of β-Hydroxybutyrate dehydrogenase (BDH1), a key enzyme in ketone body metabolism, in human pancreatic ductal adenocarcinoma (PDAC) tissues compared to adjacent normal pancreatic tissues. BDH1 promotes PDAC cell proliferation by maintaining mitochondrial acetylation levels through regulation of the intracellular NAD+/NADH ratio. These findings underscore the importance of ketone body metabolism in pancreatic cancer progression and highlight the regulatory role of BDH1 in maintaining cellular NAD+/NADH balance and mitochondrial acetylation.

Keywords:  BDH1; Ketone body; NAD(+)/NADH; Pancreatic Cancer; mitochondrial acetylation

DOI:  https://doi.org/10.1016/j.jbc.2025.110636
Biochem Soc Trans. 2025 Aug 29. 53(4): 1129-1149

Engineering protein prenylation: an emerging tool for selective protein modification.

Sneha Venkatachalapathy, Caitlin Lichtenfels, Carston R Wagner, Mark D Distefano.

  Prenyltransferases catalyze the attachment of isoprenoids to cysteine residues located near the C-termini of proteins including those containing a 'CaaX' tetrapeptide motif. This enzyme family includes farnesyl transferase (FTase), geranylgeranyltransferase type I (GGTase I), and GGTase type II (GGTase II). The CaaX motif broadly consists of cysteine (C), two aliphatic residues (a), and a variable residue (X), which determines substrate specificity for farnesylation and type I geranylgeranylation. This review primarily focuses on FTase-mediated protein modification strategies for assembling therapeutically valuable proteins. First, the process of protein prenylation and the structural features of the FTase active site are discussed. This is followed by an exploration of FTase-catalyzed bioconjugation of monomeric proteins and peptides, emphasizing its efficiency, modularity, and potential for industrial biological applications. The broader applicability of this approach is then highlighted in the design and assembly of multimeric protein structures, facilitating the development of complex biomolecular architectures with enhanced functionality, stability, and therapeutic potential. Finally, FTase mutagenesis strategies are examined that expand substrate scope, accommodating diverse functional groups for a wide range of biotechnological and therapeutic applications.

Keywords:  biocatalysis; bioconjugation; enzymatic protein modification; farnesylation; farnesyltransferase; site-specific labeling

DOI:  https://doi.org/10.1042/BST20253076
FEBS Lett. 2025 Aug 06.

C-mannosylation promotes ADAMTS1 activation and secretion in human testicular germ cell tumor NEC8 cells.

Takato Kobayashi, Takehiro Suzuki, Ryota Kawahara, Natsumi Harai, Naoshi Dohmae, Siro Simizu.

  C-mannosylation is a protein glycosylation that regulates the functions of target proteins. Although it has been reported that a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1), an important spermatogenesis factor, is C-mannosylated, the roles of C-mannosylation in ADAMTS1 in testicular cells are still unclear. In this study, we found that ADAMTS1 is C-mannosylated at Trp562 and Trp565 in testis germ NEC8 cells. To determine the roles of C-mannosylation in ADAMTS1, we established cells expressing a C-mannosylation-defective ADAMTS1, in which C-mannosylated tryptophan residues were replaced with phenylalanine residues (ADAMTS1/2WF). Processing and secretion of ADAMTS1/2WF were both inhibited compared to those of wild-type. Moreover, wild-type ADAMTS1 degraded aggrecan, whereas ADAMTS1/2WF could not. These results indicate the impact of C-mannosylation on ADAMTS1 function.

Keywords:  ADAMTS1; C‐mannosylation; protein modification; testicular germ cell tumor; vasculogenic mimicry

DOI:  https://doi.org/10.1002/1873-3468.70133
Discov Oncol. 2025 Sep 01. 16(1): 1667

N(6)-methyladenosine modification of ADGRA3 by ZC3H13 suppresses papillary thyroid cancer cell malignancy by inactivating the PI3K/Akt/mTOR signaling pathway.

Li Cai, Linghui Zhang, Zhaodan Yan.

   BACKGROUND: N(6)-methyladenosine (m6A) modification is a posttranscriptional regulatory mechanism involved in tumorigenesis. Adhesion G protein-coupled receptor A3 (ADGRA3) has been implicated in various biological processes; however, its role in papillary thyroid cancer (PTC) remains unclear. This study investigated the novel regulatory mechanism of ADGRA3 mediated by m6A modification and its effect on PTC malignancy, providing new insights into the molecular pathogenesis of PTC.
METHODS: The levels of ADGRA3 and ZC3H13 in PTC were analyzed by quantitative reverse-transcription polymerase chain reaction and Western blotting. Cell functional assays, including cell counting kit-8, wound-healing assay, and Transwell assay, were performed to assess PTC malignancy. The levels of the migration and invasion markers were detected through Western blotting. The PI3K/Akt/mTOR pathway was examined through Western blotting for pathway-associated markers. MeRIP and RNA stability assays were utilized to evaluate the regulatory effect of ZC3H13 on ADGRA3.
RESULTS: ADGRA3 was downregulated in PTC samples. ADGRA3 overexpression attenuated PTC cells to proliferate, migrate, and invade through the inhibition of the PI3K/Akt/mTOR pathway. ZC3H13 enhanced ADGRA3 mRNA stability by mediating m6A modification, and ZC3H13 knockdown reversed the tumor-suppressive effects of ADGRA3 overexpression on the malignant properties of PTC cells.
CONCLUSION: This study uncovers a novel regulatory mechanism in which ZC3H13-mediated m6A modification of ADGRA3 suppresses PTC cell malignancy by inhibiting the PI3K/Akt/mTOR pathway. These findings highlight the potential of the ZC3H13/ADGRA3 axis as a therapeutic target for PTC, offering a unique and innovative approach to PTC therapy.

Keywords:  ADGRA3; PI3K/Akt/mTOR; Papillary thyroid cancer; ZC3H13; m6A

DOI:  https://doi.org/10.1007/s12672-025-03482-3