E3泛素连接酶RNF180通过促进DNMT1的泛素化,阻止PCDH10过度甲基化,抑制胃癌细胞的增殖和转移。

IF 5.7 2区 医学 Q1 Medicine
Nannan Zhang, Xiaoliang Gao, Qiangqiang Yuan, Xin Fu, Pengliang Wang, Fenglin Cai, Hui Liu, Jing Zhang, Han Liang, Yongzhan Nie, Jingyu Deng
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引用次数: 1

摘要

背景:启动子区CpG岛的异常甲基化导致某些肿瘤抑制基因(TSGs)的下调,在包括胃癌(GC)在内的几种癌症的发生和进展中起着重要作用。原钙粘蛋白10 (PCDH10)是在多种癌症中新发现的TSG,在胃癌中下调;然而,PCDH10在GC中的具体机制尚不清楚。在这里,我们阐明了一个新的表观遗传调控信号通路,涉及E3泛素连接酶RNF180和DNA甲基转移酶1 (DNMT1),负责通过影响其启动子甲基化来调节PCDH10的表达。结果:我们发现PCDH10在胃癌细胞和组织中表达下调,PCDH10低表达与胃癌患者淋巴结转移和预后不良相关。此外,PCDH10过表达抑制胃癌细胞的增殖和转移。在机制上,dnmt1介导的启动子超甲基化导致PCDH10在GC组织和细胞中的表达降低。进一步分析发现,RNF180可以直接与DNMT1结合,并通过泛素化参与DNMT1的降解。此外,RNF180与PCDH10表达呈正相关,DNMT1与PCDH10表达呈负相关,具有重要的预后意义。结论:我们的数据显示,RNF180过表达通过泛素依赖的DNMT1降解上调PCDH10的表达,从而抑制胃癌细胞的增殖,表明RNF180/DNMT1/PCDH10轴可能是胃癌治疗的潜在靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
E3 ubiquitin ligase RNF180 prevents excessive PCDH10 methylation to suppress the proliferation and metastasis of gastric cancer cells by promoting ubiquitination of DNMT1.

Background: Downregulation of certain tumor-suppressor genes (TSGs) by aberrant methylation of CpG islands in the promoter region contributes a great deal to the oncogenesis and progression of several cancers, including gastric cancer (GC). Protocadherin 10 (PCDH10) is a newly identified TSG in various cancers and is downregulated in GC; however, the specific mechanisms of PCDH10 in GC remain elusive. Here, we elucidated a novel epigenetic regulatory signaling pathway involving the E3 ubiquitin ligase RNF180 and DNA methyltransferase 1 (DNMT1), responsible for modulating PCDH10 expression by affecting its promoter methylation.

Results: We revealed that PCDH10 was downregulated in GC cells and tissues, and low PCDH10 expression was correlated with lymph node metastasis and poor prognosis in patients with GC. Additionally, PCDH10 overexpression suppressed GC cell proliferation and metastasis. Mechanistically, DNMT1-mediated promoter hypermethylation resulted in decreased expression of PCDH10 in GC tissues and cells. Further analysis revealed that RNF180 can bind directly to DNMT1 and was involved in DNMT1 degradation via ubiquitination. Additionally, a positive correlation was found between RNF180 and PCDH10 expression and an inverse association between DNMT1 and PCDH10 expression showed considerable prognostic significance.

Conclusion: Our data showed that RNF180 overexpression upregulated PCDH10 expression via ubiquitin-dependent degradation of DNMT1, thus suppressing GC cell proliferation, indicating that the RNF180/DNMT1/PCDH10 axis could be a potential therapeutic target for GC treatment.

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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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