The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma

Cell Rep. 2017 Mar 21;18(12):2893-2906. doi: 10.1016/j.celrep.2017.02.074.

Abstract

PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers. PBRM1 loss amplified the transcriptional outputs of HIF1 and STAT3 incurred by Vhl deficiency. Analysis of mouse and human ccRCC revealed convergence on mTOR activation, representing the third driver event after genetic inactivation of VHL and PBRM1. Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC.

Keywords: HIF1; MTOR; PBRM1; STAT3; VHL; ccRCC; epigenetics; genetics; kidney cancer; mouse tumor model.

MeSH terms

  • Animals
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • DNA-Binding Proteins
  • Down-Regulation / genetics
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • HMGB Proteins / deficiency
  • HMGB Proteins / metabolism*
  • Humans
  • Hydronephrosis / genetics
  • Hydronephrosis / pathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Integrases / metabolism
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Nuclear Proteins / metabolism*
  • Oxidative Phosphorylation
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*

Substances

  • DNA-Binding Proteins
  • HMGB Proteins
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • PBRM1 protein, human
  • Pbrm1 protein, mouse
  • STAT3 Transcription Factor
  • Transcription Factors
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Mechanistic Target of Rapamycin Complex 1
  • Cre recombinase
  • Integrases
  • VHL protein, human
  • VHL protein, mouse