Dataset Information

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.

ABSTRACT: 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.

INSTRUMENT(S): timsTOF Ultra, Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Antje Richter

PROVIDER: MSV000095998 | MassIVE | Tue Oct 01 04:42:00 BST 2024

SECONDARY ACCESSION(S): PXD056422

REPOSITORIES: MassIVE

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

Arroyo Villora Sarah S Zhao Yufen Y Castellanos Silva Paula P Hahn Alba A AA Olanin Vivien V Groll David D Maurer Sandra S Roetzer Vera V Szymanski Witold W Procida-Kowalski Tara T Philipp Niklas N Koch Aline A Bartkuhn Marek M Graumann Johannes J Volckmann Richard R Koster Jan J Rossbach Oliver O Salzig Denise D Dammann Reinhard R Sigges Cornelia C Halbritter Jan J Haerteis Silke S Richter Antje Maria AM

Clinical epigenetics 20250616 1

<h4>Background</h4>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.<h4>Results</h4>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 hypermet ...[more]

PMID: 40524239

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