| First Author | Rao H | Year | 2021 |
| Journal | Cancer Res | Volume | 81 |
| Issue | 13 | Pages | 3554-3567 |
| PubMed ID | 33910928 | Mgi Jnum | J:307152 |
| Mgi Id | MGI:6719152 | Doi | 10.1158/0008-5472.CAN-20-3960 |
| Citation | Rao H, et al. (2021) Multi-level regulation of beta-catenin activity by SETD2 suppresses the transition from polycystic kidney disease to clear cell renal cell carcinoma. Cancer Res |
| abstractText | 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 beta-catenin activity at transcriptional and post-transcriptional 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-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 pre-clinical research into disease progression. |
