XIAP 通过泛素化 YTHDC1 促进膀胱癌细胞转移。

XIAP promotes metastasis of bladder cancer cells by ubiquitylating YTHDC1.

作者信息

Sun Ning, Wang Sijia, Liu Jianting, Zhang Peipei, Chang Yixin, Li Hongyan, Zhao Kun, Liu Yijie, Huang Mingzhi, Hu Yan, Lin Zhenni, Lu Yongyong, Jiang Guosong, Chen Wei, Huang Chuanshu, Jin Honglei

机构信息

Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

出版信息

Cell Death Dis. 2025 Mar 25;16(1):205. doi: 10.1038/s41419-025-07545-9.

DOI:10.1038/s41419-025-07545-9

PMID:40133252

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11937301/

Abstract

X-linked inhibitor of apoptosis protein (XIAP), a member of the IAP family, is overexpressed in a variety of tumors and plays an important role in tumor progression. Increasing evidence suggests that XIAP promotes metastasis of bladder cancer but the underlying mechanism is not very clear. The RNA N6-methyladenosine (mA) reader YTHDC1 regulates RNA splicing, nuclear transport, and mRNA stability and is a potential tumor target; however, its ubiquitin E3 ligase has not been described. In this study, screening of proteins that specifically interact with XIAP identified YTHDC1 as its degradation substrate. Ectopic overexpression of XIAP promoted degradation of YTHDC1, and knockout of XIAP upregulated YTHDC1, which inhibited metastasis of bladder cancer. Furthermore, YTHDC1 reduced the expression of matrix metalloproteinase-2 (MMP-2) by destabilizing its mRNA. These experiments revealed that XIAP promotes ubiquitination of YTHDC1, positively regulating expression of the MMP-2 and promoting metastasis of bladder cancer. Collectively, these findings demonstrate that XIAP is a critical regulator of YTHDC1 and pinpoint the XIAP/YTHDC1/MMP-2 axis as a promising target for the treatment of bladder cancer.

摘要

X连锁凋亡抑制蛋白（XIAP）是IAP家族的成员之一，在多种肿瘤中过表达，并在肿瘤进展中发挥重要作用。越来越多的证据表明，XIAP促进膀胱癌转移，但其潜在机制尚不清楚。RNA N6-甲基腺苷（m⁶A）阅读器YTHDC1调节RNA剪接、核转运和mRNA稳定性，是一个潜在的肿瘤靶点；然而，其泛素E3连接酶尚未见报道。在本研究中，通过筛选与XIAP特异性相互作用的蛋白质，确定YTHDC1为其降解底物。XIAP的异位过表达促进了YTHDC1的降解，而XIAP的敲除上调了YTHDC1，抑制了膀胱癌的转移。此外，YTHDC1通过使其mRNA不稳定来降低基质金属蛋白酶2（MMP-2）的表达。这些实验表明，XIAP促进YTHDC1的泛素化，正向调节MMP-2的表达并促进膀胱癌转移。总的来说，这些发现表明XIAP是YTHDC1的关键调节因子，并指出XIAP/YTHDC1/MMP-2轴是治疗膀胱癌的一个有前景的靶点。