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

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

Gao W1, Li W2,3, Xiao T1,2,3, Liu XS2,3, Kaelin WG Jr4,5.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
2
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215.
3
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA 02115.
4
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; william_kaelin@dfci.harvard.edu.
5
Howard Hughes Medical Institute, Chevy Chase, MD 20815.

Abstract

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

PMID:
28082722
PMCID:
PMC5293026
DOI:
10.1073/pnas.1619726114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

W.G.K. receives consulting income and equity from Peloton Therapeutics, which is developing HIF2 inhibitors for treatment of kidney cancer.

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