bims-meprid 2025-03-30 papers

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

Commun Biol. 2025 Mar 21. 8(1): 471

KLHL25-ACLY module functions as a switch in the fate determination of the differentiation of iTreg/Th17.

Miaomiao Tian, Fengqi Hao, Xin Jin, Xinyu Wang, Tianyi Chang, Shuang He, Huiyue Wang, Ying Jiang, Yang Wang, Jia Liu, Yunpeng Feng, Dan Li, Zhinan Yin, Xueqing Ba, Min Wei.

The differentiation of Th17 and iTreg is tightly associated with fatty acid metabolism. TGFβ1-induced iTreg differentiation from Th0 relies on fatty acid oxidation (FAO), whereas IL-6 with TGFβ1 shifts metabolism to Th17-preferred fatty acid synthesis (FAS). However, how IL-6 reprograms fatty acid metabolism remains unclear. Here, we unveiled that TGFβ1-activated JNK is recruited to the Klhl25 promoter by NF-YA. JNK then phosphorylates histone H3 at Ser10 to activate Klhl25 transcription, leading to the ubiquitination-dependent degradation of ATP-citrate lyase (ACLY) and the switch from FAS to FAO, which supports iTreg generation. Whereas, upon IL-6 signaling, NF-YA is phosphorylated by ERK, losing its DNA binding ability, which shuts off TGFβ1-JNK-mediated Klhl25 transcription and ACLY ubiquitination, thereby increasing FAS and supporting Th17 differentiation. This study demonstrated that KLHL25-ACLY module functions as a switch in response to TGFβ1 and IL-6 signals, playing a decisive role in the fate determination of iTreg/Th17 differentiation.

DOI: https://doi.org/10.1038/s42003-025-07917-z

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

Cancer Res. 2025 Mar 26.

Cancer-Associated Fibroblasts Foster a High-Lactate Microenvironment to Drive Perineural Invasion in Pancreatic Cancer.

Tingting Li, Chonghui Hu, Tianhao Huang, Yu Zhou, Qing Tian, Huimou Chen, Rihua He, Yuan Yuan, Yong Jiang, Honghui Jiang, Kaijun Huang, Di Cheng, Rufu Chen, Shangyou Zheng.

Perineural invasion (PNI) is a pivotal prognostic factor in pancreatic cancer associated with aggressive tumor behavior and adverse patient outcomes. The recognized clinical impact of PNI highlights the need to better understand the molecular mechanisms underlying PNI-induced phenotypes. In this study, we isolated PNI-associated cancer-associated fibroblasts (pCAFs), which demonstrated a markedly enhanced capacity to promote neural invasion in pancreatic cancer compared to non-perineural invasion-associated CAFs (npCAFs). Single-cell, high-throughput sequencing and metabolomics data showed a significant upregulation of glycolysis in pCAFs, fostering a high-lactate tumor microenvironment conducive to cancer progression. pCAF-derived lactate was absorbed by tumor cells, facilitating histone H3K18 lactylation. The lactate-induced epigenetic modification activated the transcription of neural invasion-associated genes, such as L1CAM and SLIT1, thereby driving PNI in pancreatic cancer. Further exploration of metabolic reprogramming in pCAFs revealed enhanced acetylation of the glycolytic enzyme GAPDH, which correlated with increased enzymatic activity and glycolytic flux. Targeting of GAPDH and lactylation modifications significantly inhibited neural invasion in a genetically engineered mouse model. Clinical data suggested that high levels of H3K18 lactylation correlate with severe PNI and poorer patient prognosis. Together, these findings provide critical insights into the role of CAFs in promoting PNI of pancreatic cancer, highlighting glycolytic reprogramming and lactate-driven histone modifications as potential therapeutic targets for PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3173