The SWI/SNF protein PBRM1 restrains VHL-loss-driven clear cell renal cell carcinoma Journal Article

Authors: Nargund, A. M.; Pham, C. G.; Dong, Y.; Wang, P. I.; Osmangeyoglu, H. U.; Xie, Y.; Aras, O.; Han, S.; Oyama, T.; Takeda, S.; Ray, C. E.; Dong, Z.; Berge, M.; Hakimi, A. A.; Monette, S.; Lekaye, C. L.; Koutcher, J. A.; Leslie, C. S.; Creighton, C. J.; Weinhold, N.; Lee, W.; Tickoo, S. K.; Wang, Z.; Cheng, E. H.; Hsieh, J. J.
Article Title: The SWI/SNF protein PBRM1 restrains VHL-loss-driven clear cell renal cell carcinoma
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. © 2017 The Author(s)
Keywords: genetics; epigenetics; kidney cancer; mtor; stat3; vhl; pbrm1; ccrcc; hif1; mouse tumor model
Journal Title: Cell Reports
Volume: 18
Issue: 12
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2017-03-21
Start Page: 2893
End Page: 2906
Language: English
DOI: 10.1016/j.celrep.2017.02.074
PROVIDER: scopus
PUBMED: 28329682
PMCID: PMC5431084
Notes: Article -- Export Date: 2 May 2017 -- Source: Scopus
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MSK Authors
  1. Satish K Tickoo
    369 Tickoo
  2. Hongbiao Carl Lekaye
    23 Lekaye
  3. Jason A Koutcher
    235 Koutcher
  4. Sebastien Monette
    76 Monette
  5. Yiyu Dong
    16 Dong
  6. Shugaku Takeda
    16 Takeda
  7. Emily H Cheng
    55 Cheng
  8. Christina Leslie
    109 Leslie
  9. Toshinao Oyama
    6 Oyama
  10. Can Gia Pham
    8 Pham
  11. William Lee
    38 Lee
  12. Abraham Ari Hakimi
    129 Hakimi
  13. Omer Aras
    29 Aras
  14. Patricia Ibai Wang
    12 Wang
  15. Song   Han
    5 Han
  16. Yuchen Xie
    2 Xie
  17. Chelsea Elizabeth Ray
    2 Ray
  18. Zhenghong Dong
    1 Dong
  19. Mathieu Berge
    1 Berge