Requirement for Cyclin D1 Underlies Cell-Autonomous HIF2 Dependence in Kidney Cancer.

ABSTRACT: Inactivation of the VHL gene stabilizes HIF2α, which drives clear-cell renal cell carcinoma (ccRCC). The HIF2α inhibitor belzutifan is approved for ccRCC treatment, but de novo and acquired resistance are common. HIF2α, bound to ARNT, transcriptionally activates many genes. We performed CRISPR-mediated gene activation screens in HIF2α-dependent ccRCC lines treated with a belzutifan analog to identify HIF2α-responsive genes that confer cell-autonomous belzutifan resistance when not downregulated. Sustaining the expression of the HIF2α target gene CCND1, encoding cyclin D1, promoted HIF2α independence/belzutifan resistance. This activity requires CDK4/6 activation by cyclin D1 but is not solely due to phosphorylation of the canonical cyclin D1 target, pRB. Indeed, ccRCC lines lacking all thr

SUBMITTER: Shirole NH 

PROVIDER: S-EPMC12223508 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature