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

Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):1027-1032. doi: 10.1073/pnas.1619726114. Epub 2017 Jan 12.


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.

Keywords: BAF180; PBAF; chromatin; hypoxia; kidney cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • DNA-Binding Proteins
  • Frameshift Mutation
  • Gene Expression Regulation, Neoplastic*
  • Genes, Tumor Suppressor*
  • Heterografts
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Mice, Nude
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / deficiency
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Recombinant Proteins / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Transcription, Genetic
  • Transcriptome
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics


  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Neoplasm Proteins
  • Nuclear Proteins
  • PBRM1 protein, human
  • RNA, Small Interfering
  • Recombinant Proteins
  • Transcription Factors
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human