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

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

doi:10.1038/s41419-024-07227-y

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

Cell Death Dis. 2024 Nov 14;15(11):825. doi: 10.1038/s41419-024-07227-y.

Authors

Jie Liu^#^{1

2}, Xujin Wei^#³, Yixuan Xie¹, Yuxiang Yan⁴, Sihui Xue¹, Xiangyu Wang², Han Chen¹, Qilong Pan¹, Sisi Yan¹, Xiaoling Zheng⁵, Qingling Huang⁶

Affiliations

¹ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
² Department of Endoscopic Center, The Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China.
³ Endoscopic Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
⁴ Fujian Key Laboratory of Oral Diseases, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China.
⁵ Department of Endoscopic Center, The Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China. [email protected].
⁶ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. [email protected].

^# Contributed equally.

PMID: 39543140
DOI: 10.1038/s41419-024-07227-y

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.

Abstract

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