Epigenetic silencing and CRISPR-mediated reactivation of tight junction protein claudin10b (CLDN10B) in renal cancer.

IF 4.8 2区医学 Q1 GENETICS & HEREDITY

Clinical Epigenetics Pub Date : 2025-06-16 DOI:10.1186/s13148-025-01911-2

Sarah Arroyo Villora, Yufen Zhao, Paula Castellanos Silva, Alba A Hahn, Vivien Olanin, David Groll, Sandra Maurer, Vera Roetzer, Witold Szymanski, Tara Procida-Kowalski, Niklas Philipp, Aline Koch, Marek Bartkuhn, Johannes Graumann, Richard Volckmann, Jan Koster, Oliver Rossbach, Denise Salzig, Reinhard Dammann, Cornelia Sigges, Jan Halbritter, Silke Haerteis, Antje Maria Richter

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引用次数: 0

Abstract

Background: The kidney's tubular system relies on cell polarity and tight junctions to maintain structure and function and disruptions contribute to diseases like cancer. Loss of tight junction proteins such as Claudins can actively contribute to tumorigenesis.

Results: We aimed to identify biomarkers for renal carcinoma, after kidney transplantation and conventional kidney tumors. We identified the epigenetic silencing of the Claudin 10 gene isoform B (CLDN10B) through DNA hypermethylation in renal cancers, including clear cell (ccRCC), papillary (pRCC) and post-transplantation renal carcinoma (PT-ccRCC). In contrast, CLDN10A was hypomethylated in ccRCC and pRCC. Differential methylation of the isoforms discriminates RCC from other malignancies. The epigenetic alteration of CLDN10B significantly correlated with reduced patient survival and advanced tumor staging. CLDN10B overexpression or induction significantly inhibited migration, cell cycle progression, and cellular growth. Using a CRISPR-based epigenetic editing tool reactivated CLDN10B to its endogenous level using VP160 and TET1 by promoter demethylation and significantly demonstrated its tumor-suppressive effects in 2D and 3D cell models.

Conclusion: Our findings suggest that CLDN10B acts as a tumor suppressor, and its epigenetic regulation may represent a therapeutic target for RCC. Ultimately, understanding CLDN10B's regulation and function could provide new insights into renal cancer treatment.

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肾癌中紧密连接蛋白CLDN10B （CLDN10B）的表观遗传沉默和crispr介导的再激活

背景：肾小管系统依赖于细胞极性和紧密连接来维持结构和功能，破坏会导致癌症等疾病。紧密连接蛋白（如Claudins）的缺失可以积极促进肿瘤的发生。结果：我们旨在鉴别肾移植后肾癌和常规肾肿瘤的生物标志物。我们在肾透明细胞癌（ccRCC）、乳头状肾癌（pRCC）和移植后肾癌（PT-ccRCC）中通过DNA超甲基化发现了Claudin 10基因异构体B （CLDN10B）的表观遗传沉默。相比之下，CLDN10A在ccRCC和pRCC中低甲基化。同种异构体的差异甲基化将RCC与其他恶性肿瘤区分开来。CLDN10B的表观遗传改变与患者生存率降低和肿瘤分期进展显著相关。CLDN10B过表达或诱导可显著抑制迁移、细胞周期进程和细胞生长。使用基于crispr的表观遗传编辑工具，使用VP160和TET1通过启动子去甲基化将CLDN10B重新激活到内源性水平，并在2D和3D细胞模型中显著显示其肿瘤抑制作用。结论：我们的研究结果表明，CLDN10B具有肿瘤抑制作用，其表观遗传调控可能是RCC的治疗靶点。最终，了解CLDN10B的调控和功能可以为肾癌的治疗提供新的见解。

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来源期刊

Clinical Epigenetics ONCOLOGY-

自引率

5.30%

发文量

150

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.