The ubiquitin ligase STUB1 suppresses tumorigenesis of renal cell carcinomas through regulating YTHDF1 stability.

IF 3.3 3区 医学 Q2 ONCOLOGY
Siquan Ma, Yi Sun, Guoyao Gao, Jin Zeng, Ke Chen, Zhenyu Zhao
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引用次数: 0

Abstract

STIP1 homology and U-box protein 1 (STUB1), a crucial member of the RING family E3 ubiquitin ligase, serves dual roles as an oncogene and a tumor suppressor in various human cancers. However, the role and mechanism of STUB1 in clear cell renal cell carcinoma (ccRCC) remain poorly defined. Here, we identified YTHDF1 as a novel STUB1 interaction partner using affinity purification mass spectrometry (AP-MS). Furthermore, we revealed that STUB1 promotes the ubiquitination and degradation of YTHDF1. Consequently, STUB1 depletion leads to YTHDF1 up-regulation in renal cancer cells. Functionally, STUB1 depletion promoted migration and invasion of ccRCC cells in a YTHDF1-dependent manner. Additionally, depletion of STUB1 also increased the tumorigenic potential of ccRCC in a xenograft model. Importantly, STUB1 expression is down-regulated in ccRCC tissues, and its low expression level correlates with advanced tumor stage and poor overall survival in ccRCC patients. Taken together, these findings reveal that STUB1 inhibits the tumorigenicity of ccRCC by regulating YTHDF1 stability.

泛素连接酶STUB1通过调节YTHDF1的稳定性抑制肾细胞癌的肿瘤发生。
STIP1 同源物和 U-box 蛋白 1(STUB1)是 RING 家族 E3 泛素连接酶的重要成员,在多种人类癌症中扮演着致癌基因和肿瘤抑制因子的双重角色。然而,STUB1 在透明细胞肾细胞癌(ccRCC)中的作用和机制仍未明确。在这里,我们利用亲和纯化质谱(AP-MS)鉴定出了 YTHDF1 作为 STUB1 的新型相互作用伙伴。此外,我们还发现 STUB1 促进了 YTHDF1 的泛素化和降解。因此,消耗 STUB1 会导致 YTHDF1 在肾癌细胞中上调。从功能上讲,STUB1的缺失以YTHDF1依赖的方式促进了ccRCC细胞的迁移和侵袭。此外,在异种移植模型中,消耗 STUB1 还会增加 ccRCC 的致瘤潜力。重要的是,STUB1 在 ccRCC 组织中表达下调,其低表达水平与 ccRCC 患者的肿瘤晚期和总生存率低相关。综上所述,这些发现揭示了 STUB1 通过调节 YTHDF1 的稳定性来抑制 ccRCC 的致瘤性。
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
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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