MassIVE MSV000095998

Partial Public PXD056422

Epigenetic silencing of tight junction protein CLDN10B in renal cancer including post-transplantation RCC and its endogenous reactivation by CRISPR results in cell growth suppression.

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Description

Background The kidney's tubular system, composed of nephrons and collecting ducts, relies on cellular planar polarity and tight junctions to maintain structure and function. Disruptions in this polarity contribute to diseases like cystic kidney disease and cancer. Tight junctions, such as those formed by Claudin proteins, are critical for cellular polarity and tissue organization. Therefore, epigenetically inactivated Claudins can actively contribute to tumorigenesis. Results In this study, we identified the epigenetic silencing of Claudin 10B (CLDN10B) through DNA hypermethylation in renal cancers, including clear cell renal carcinoma (ccRCC) and post-transplantation malignancies (PT-RCC). Hypermethylation selectively affected CLDN10B, while the related isoform, CLDN10A, was hypomethylated in clear cell and papillary RCC. Differential methylation of the Isoforms can serve as a discriminator of RCC from other malignancies. The epigenetic alteration of CLDN10B significantly correlated with reduced patient survival and advanced tumor staging. CLDN10B overexpression and CLDN10B induction via an inducible cell line significantly inhibited migration, cell cycle progression, and cellular growth. We further investigated CLDN10B using CRISPR-based epigenetic editing to reactivate CLDN10B to its endogenous level. Targeting the CLDN10B promoter with VP160 and TET1 in a dCas9-system effectively demethylated, significantly restored its expression and 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. Ultimately, understanding CLDN10Bs regulation and function could provide new insights into renal cancer treatment. [doi:10.25345/C5NK36H32] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: epigenetic, cancer, DIA, Claudin, tumor suppression, TimsTof Ultra, Exploris ; CLDN10, renal cell carcinoma (RCC), DNA (hyper)methylation, epigenetic editing, CRISPR-Cas9

Contact

Principal Investigators:
(in alphabetical order) 		Antje Richter, Institute for Genetics, Justus-Liebig-University Giessen, 35390 Giessen, Germany
Submitting User: Wszymanski

Publications

Arroyo Villora S, Zhao Y, Castellanos Silva P, Hahn AA, Olanin V, Groll D, Maurer S, Roetzer V, Szymanski W, Procida-Kowalski T, Philipp N, Koch A, Bartkuhn M, Graumann J, Volckmann R, Koster J, Rossbach O, Salzig D, Dammann R, Sigges C, Halbritter J, Haerteis S, Richter AM.
Epigenetic silencing and CRISPR-mediated reactivation of tight junction protein claudin10b (CLDN10B) in renal cancer.
Clin Epigenetics. 2025 Jun 16;17(1):102. Epub 2025 Jun 16.

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