USP49 promotes adenocarcinoma of the esophagogastric junction malignant progression via activating SHCBP1-β-catenin-GPX4 axis.

IF 3.3 3区 医学 Q2 ONCOLOGY
Yun Ding, Zhen Liu, Xiaofeng Dai, Ruiwen Ruan, Hongguang Zhong, Zhipeng Wu, Yangyang Yao, Jun Chen, Jun Deng, Jianping Xiong
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引用次数: 0

Abstract

Adenocarcinoma of the esophagogastric junction (AEG) has received widespread attention because of its increasing incidence. However, the molecular mechanism underlying tumor progression remains unclear. Here, we report that the downregulation of Ubiquitin-specific peptidase 49 (USP49) promotes ferroptosis in OE33 and OE19 cells, thereby inhibiting cell proliferation in vitro and in vivo, whereas the overexpression of USP49 had the opposite effect. In addition, USP49 downregulation promoted AEG cell radiotherapy sensitivity. Moreover, overexpression of Glutathione PeroXidase 4 (GPX4) reversed the ferroptosis and proliferation inhibition induced by USP49 knockdown. Mechanistically, USP49 deubiquitinates and stabilizes Shc SH2-domain binding protein 1 (SHCBP1), subsequently facilitating the entry of β-catenin into the nucleus to enhance GPX4 transcriptional expression. Finally, high USP49 expression was correlated with shorter overall survival in patients with AEG. In summary, our findings identify USP49 as a novel regulator of ferroptosis in AEG cells, indicating that USP49 may be a potential therapeutic target in AEG.

USP49 通过激活 SHCBP1-β-catenin-GPX4 轴促进食管胃交界处腺癌的恶性发展。
食管胃交界处腺癌(AEG)因其发病率不断上升而受到广泛关注。然而,肿瘤进展的分子机制仍不清楚。在这里,我们报告了泛素特异性肽酶 49(USP49)的下调会促进 OE33 和 OE19 细胞的铁凋亡,从而抑制细胞在体外和体内的增殖,而 USP49 的过表达则具有相反的作用。此外,USP49 的下调促进了 AEG 细胞对放疗的敏感性。此外,过表达谷胱甘肽过氧化物酶 4(GPX4)可逆转 USP49 下调诱导的铁变态反应和增殖抑制。从机理上讲,USP49 会去泛素化并稳定 Shc SH2 域结合蛋白 1(SHCBP1),从而促进 β-catenin 进入细胞核,增强 GPX4 的转录表达。最后,USP49的高表达与AEG患者较短的总生存期相关。总之,我们的研究结果表明 USP49 是 AEG 细胞中铁细胞凋亡的新型调节因子,这表明 USP49 可能是 AEG 的潜在治疗靶点。
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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