Multilevel Regulation of β-Catenin Activity by SETD2 Suppresses the Transition from Polycystic Kidney Disease to Clear Cell Renal Cell Carcinoma

Patients with polycystic kidney disease (PKD) are at a high risk of developing renal cell carcinoma (RCC). However, little is known about genetic alterations or changes in signaling pathways during the transition from PKD to RCC. SET domain-containing 2 (SETD2) is a histone methyltransferase, which catalyzes trimethylation of H3K36 (H3K36me3) and has been identified as a tumor suppressor in dear cell renal cell carcinoma (ccRCC), but the underlying mechanism remains largely unexplored. Here we report that knockout of SETD2 in a c-MYC-driven PKD mouse model drove the transition to ccRCC. SETD2 inhibited beta-catenin activity at transcriptional and posttranscriptional levels by competing with beta-catenin for binding promoters of target genes and maintaining transcript levels of members of the beta-catenin destruction complex. Thus, SETD2 deficiency enhanced the epithelial-to-mesenchymal transition and tumorigenesis through the hyperactivation of Wnt/beta-catenin signaling. Our findings reveal previously unrecognized roles of SETD2-mediated competitive DNA binding and H3K36me3 modification in regulating Wnt/beta-catenin signaling during the transition from PKD to ccRCC. The novel autochthonous mouse models of PKD and ccRCC will be useful for predinical research into disease progression. Significance: These findings characterize multiple mechanisms by which SETD2 inhibits beta-catenin activity during the transition of polycystic kidney disease to renal cell carcinoma, providing a potential therapeutic strategy for high-risk patients.

Automated summary

This study reveals that SETD2 inhibits beta-catenin activity during the transition from polycystic kidney disease (PKD) to renal cell carcinoma (RCC) by competing with beta-catenin for binding promoters of target genes, ultimately enhancing Wnt/beta-catenin signaling and promoting epithelial-to-mesenchymal transition and tumorigenesis.