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

Amrita M. Nargund, Can G. Pham, Yiyu Dong, Patricia I. Wang, Hatice U. Osmangeyoglu, Yuchen Xie, Omer Aras, Song Han, Toshinao Oyama, Shugaku Takeda, Chelsea E. Ray, Zhenghong Dong, Mathieu Berge, A. Ari Hakimi, Sebastien Monette, Carl L. Lekaye, Jason A. Koutcher, Christina S. Leslie, Chad J. Creighton, Nils WeinholdWilliam Lee, Satish K. Tickoo, Zhong Wang, Emily H. Cheng, James J. Hsieh

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

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.

Original languageEnglish
Pages (from-to)2893-2906
Number of pages14
JournalCell Reports
Volume18
Issue number12
DOIs
StatePublished - Mar 21 2017

Keywords

  • HIF1
  • MTOR
  • PBRM1
  • STAT3
  • VHL
  • ccRCC
  • epigenetics
  • genetics
  • kidney cancer
  • mouse tumor model

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