MDM4 inhibits ferroptosis in p53 mutant colon cancer via regulating TRIM21/GPX4 expression.

IF 8.1 1区生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2024-11-14 DOI:10.1038/s41419-024-07227-y

Jie Liu, Xujin Wei, Yixuan Xie, Yuxiang Yan, Sihui Xue, Xiangyu Wang, Han Chen, Qilong Pan, Sisi Yan, Xiaoling Zheng, Qingling Huang

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Abstract

MDM4 is one of the major regulators of p53. The biological effect of MDM4 on tumor is controversial, its role and molecular mechanism in colon cancer progression and prognosis are still unclear. In this study, we identify that MDM4 is significantly overexpressed in human colon cancer and high MDM4 expression was associated with poor prognosis of colon cancer with mutant p53. MDM4 inhibits the ubiquitination of the ferroptosis marker protein GPX4 at K167 and K191 by upregulating the protein expression level of the E3 ubiquitin ligase TRIM21, which promotes the polyubiquitination of GPX4 transfer from K48- to K63- linked ubiquitination. Thereby, MDM4 enhances the stability of GPX4 protein, inhibiting ferroptosis, increasing the resistance of colon cancer patients to chemotherapy, and promoting colon cancer progression. These findings elucidate the ferroptosis inhibition effect of MDM4 via regulating TRIM21/GPX4 on p53-mutated colon cancer and provide a potential therapeutic strategy for colon cancer therapy.

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MDM4通过调节TRIM21/GPX4的表达抑制p53突变结肠癌中的铁变态反应。

MDM4 是 p53 的主要调控因子之一。MDM4对肿瘤的生物学效应尚存争议，其在结肠癌进展和预后中的作用和分子机制仍不清楚。本研究发现，MDM4在人类结肠癌中显著过表达，MDM4的高表达与p53突变的结肠癌的不良预后相关。MDM4通过上调E3泛素连接酶TRIM21的蛋白表达水平来抑制铁突变标志蛋白GPX4在K167和K191处的泛素化，从而促进GPX4的多泛素化从K48链接泛素化转移到K63链接泛素化。因此，MDM4 增强了 GPX4 蛋白的稳定性，抑制了铁凋亡，增加了结肠癌患者对化疗的耐药性，促进了结肠癌的进展。这些发现阐明了 MDM4 通过调控 TRIM21/GPX4 对 p53 突变结肠癌的铁氧化抑制作用，为结肠癌治疗提供了一种潜在的治疗策略。

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

Cell Death & Disease CELL BIOLOGY-

CiteScore

15.10

自引率

2.20%

发文量

935

审稿时长

2 months

期刊介绍： Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism