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Sci Transl Med. 2017 Jul 12;9(398). pii: eaal5272. doi: 10.1126/scitranslmed.aal5272.

HIF activation causes synthetic lethality between the VHL tumor suppressor and the EZH1 histone methyltransferase.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
2
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
3
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4
Center for Cancer Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
5
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA. william_kaelin@dfci.harvard.edu.
6
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
7
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

Abstract

Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) is the signature lesion in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). pVHL loss causes the transcriptional activation of hypoxia-inducible factor (HIF) target genes, including many genes that encode histone lysine demethylases. Moreover, chromatin regulators are frequently mutated in this disease. We found that ccRCC displays increased H3K27 acetylation and a shift toward mono- or unmethylated H3K27 caused by an HIF-dependent increase in H3K27 demethylase activity. Using a focused short hairpin RNA library, as well as CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) and a pharmacological inhibitor, we discovered that pVHL-defective ccRCC cells are hyperdependent on the H3K27 methyltransferase EZH1 for survival. Therefore, targeting EZH1 could be therapeutically useful in ccRCC.

PMID:
28701475
PMCID:
PMC6039096
DOI:
10.1126/scitranslmed.aal5272
[Indexed for MEDLINE]
Free PMC Article

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