Funding
Ministry of Science and Technology of the People's Republic of China
National Natural Science Foundation of China
State Key Laboratory of Oncogenes and Related Genes
Science and Technology Commission of Shanghai Municipality
111 project
Innovation Research Plan from Shanghai Municipal Education Commission
Shenzhen Basic Research Foundation
Guangdong Province Basic Research Foundation
ARTICLE ABSTRACT
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 tri-methylation of H3K36 (H3K36me3) and has been identified as a tumor suppressor in clear 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 β-catenin activity at transcriptional and posttranscriptional levels by competing with β-catenin for binding promoters of target genes and maintaining transcript levels of members of the β-catenin destruction complex. Thus, SETD2 deficiency enhanced the epithelial-to-mesenchymal transition and tumorigenesis through the hyperactivation of Wnt/β-catenin signaling. Our findings reveal previously unrecognized roles of SETD2-mediated competitive DNA binding and H3K36me3 modification in regulating Wnt/β-catenin signaling during the transition from PKD to ccRCC. The novel autochthonous mouse models of PKD and ccRCC will be useful for preclinical research into disease progression.
These findings characterize multiple mechanisms by which SETD2 inhibits β-catenin activity during the transition of polycystic kidney disease to renal cell carcinoma, providing a potential therapeutic strategy for high-risk patients.
