Villora Sarah Arroyo, Zhao Yufen, Silva Paula Castellanos, Hahn Alba A, Olanin Vivien, Groll David, Maurer Sandra, Roetzer Vera, Szymanski Witold, Procida-Kowalski Tara, Philipp Niklas, Koch Aline, Bartkuhn Marek, Graumann Johannes, Volckmann Richard, Koster Jan, Rossbach Oliver, Salzig Denise, Dammann Reinhard, Sigges Cornelia, Halbritter Jan, Haerteis Silke, Richter Antje Maria
Institute for Genetics, Justus-Liebig-University Giessen, Heinrich-Buff Ring 58, 35390, Giessen, Germany.
Institute for Molecular and Cellular Anatomy, University of Regensburg, 93053, Regensburg, Germany.
Clin Epigenetics. 2025 Jun 16;17(1):102. doi: 10.1186/s13148-025-01911-2.
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.
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.
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.
肾脏的肾小管系统依赖细胞极性和紧密连接来维持结构和功能，而这些结构的破坏会导致癌症等疾病。紧密连接蛋白如Claudins的缺失会积极促进肿瘤发生。
我们旨在识别肾移植后肾癌和传统肾肿瘤的生物标志物。我们通过DNA高甲基化在包括透明细胞癌（ccRCC）、乳头状癌（pRCC）和移植后肾癌（PT-ccRCC）在内的肾癌中鉴定出Claudin 10基因亚型B（CLDN10B）的表观遗传沉默。相比之下，CLDN10A在ccRCC和pRCC中呈低甲基化。这些亚型的差异甲基化可将肾癌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的过表达或诱导显著抑制迁移、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，通过启动子去甲基化将CLDN10B重新激活至其内源水平，并在2D和3D细胞模型中显著证明了其肿瘤抑制作用。
我们的研究结果表明CLDN10B作为一种肿瘤抑制因子，其表观遗传调控可能代表肾癌的一个治疗靶点。最终，了解CLDN10B的调控和功能可为肾癌治疗提供新的见解。
