Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL−/− clear cell renal carcinoma

Significance Mutational inactivation of the VHL tumor suppressor gene is the signature lesion in the most common form of kidney cancer and causes inappropriate accumulation of the HIF transcription factor, which activates genes that normally facilitate adaptation to hypoxia but, in the context of kidney cancer, also promote tumorigenesis. Additional mutational events are needed, in conjunction with VHL loss, to cause kidney cancer. The most common of these are inactivating mutations of the PBRM1 tumor suppressor gene, which encodes a component [BRG1-associated factor 180 (BAF180)] of a multiprotein complex [Polybromo- and BRG1-associated factors-containing complex (PBAF)] that regulates the positions of nucleosomes throughout the genome. We describe here kidney cancer cell-based models for monitoring BAF180 function and show that loss of BAF180 accentuates the transcriptional response to HIF. Most clear cell renal carcinomas (ccRCCs) are initiated by somatic inactivation of the VHL tumor suppressor gene. The VHL gene product, pVHL, is the substrate recognition unit of an ubiquitin ligase that targets the HIF transcription factor for proteasomal degradation; inappropriate expression of HIF target genes drives renal carcinogenesis. Loss of pVHL is not sufficient, however, to cause ccRCC. Additional cooperating genetic events, including intragenic mutations and copy number alterations, are required. Common examples of the former are loss-of-function mutations of the PBRM1 and BAP1 tumor suppressor genes, which occur in a mutually exclusive manner in ccRCC and define biologically distinct subsets of ccRCC. PBRM1 encodes the Polybromo- and BRG1-associated factors-containing complex (PBAF) chromatin remodeling complex component BRG1-associated factor 180 (BAF180). Here we identified ccRCC lines whose ability to proliferate in vitro and in vivo is sensitive to wild-type BAF180, but not a tumor-associated BAF180 mutant. Biochemical and functional studies linked growth suppression by BAF180 to its ability to form a canonical PBAF complex containing BRG1 that dampens the HIF transcriptional signature.