PRMT5 K240lac confers ferroptosis resistance via ALKBH5/SLC7A11 axis in colorectal cancer.

IF 6.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Oncogene Pub Date : 2025-05-30 DOI:10.1038/s41388-025-03457-2

Shuang Qu, Baijie Feng, Mengying Xing, Yingyi Qiu, Longjun Ma, Zhou Yang, Yi Ji, Feng Huang, Yuanrong Wang, Jingwan Zhou, Min Xu, Jiaxin He, Qinyao Zhou, Xin Zhou, Wenjing Xiong, Bing Yao, Ming Liu, Qiantong Dong, Liu Yang, Shouyong Gu

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Abstract

Ferroptosis is a newly discovered type of regulated cell death, characterized by the iron-dependent accumulation of lipid reactive oxygen species, which has been implicated in a number of human diseases. However, the regulatory mechanisms underlying ferroptosis in colorectal cancer (CRC) remain unclear. In this study, we unravel the pivotal role of PRMT5 in the progression of CRC by promoting ferroptosis resistance. Mechanistically, PRMT5 directly inhibits the transcription of m⁶A demethylase ALKBH5 via histone modifications (H4R3me2s and H3R8me2s), bolstering SLC7A11 mRNA stability and expression, thereby aggravating CRC progression through attenuating ferroptosis. Particularly, our work identifies PRMT5 as a novel lactylation substrate at lysine 240 (PRMT5 K240lac), crucial for sustaining CRC ferroptosis resistance by shaping the ALKBH5/SLC7A11 axis, while mutation disrupting these effects. Overall, our work underscores the significance of PRMT5 K240lac in conferring ferroptosis resistance in CRC, proposing targeted intervention along the PRMT5 K240lac/ALKBH5/SLC7A11 axis as an innovative therapeutic approach in CRC treatment.

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PRMT5 K240lac通过ALKBH5/SLC7A11轴在结直肠癌中赋予铁凋亡抗性。

铁死亡是一种新发现的受调控的细胞死亡类型，其特征是脂质活性氧的铁依赖性积累，这与许多人类疾病有关。然而，结直肠癌（CRC）中铁下垂的调控机制尚不清楚。在这项研究中，我们揭示了PRMT5通过促进铁下垂抵抗在结直肠癌进展中的关键作用。在机制上，PRMT5通过组蛋白修饰（H4R3me2s和H3R8me2s）直接抑制m6A去甲基化酶ALKBH5的转录，增强SLC7A11 mRNA的稳定性和表达，从而通过减轻铁垂加重CRC的进展。特别是，我们的工作确定PRMT5是赖氨酸240 （PRMT5 K240lac）的新型乳酸化底物，通过塑造ALKBH5/SLC7A11轴来维持CRC铁凋亡抗性至关重要，而突变破坏了这些作用。总的来说，我们的工作强调了PRMT5 K240lac在CRC中赋予铁下沉抗性的重要性，并提出沿PRMT5 K240lac/ALKBH5/SLC7A11轴的靶向干预作为CRC治疗的创新治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.