@article{7bdddafb85a84fa5aa4935a5976a7782,
title = "HIF activation causes synthetic lethality between the VHL tumor suppressor & the EZH1 histone methyltransferase",
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.",
author = "Chakraborty, {Abhishek A.} and Eijiro Nakamura and Jun Qi and Amanda Creech and Jaffe, {Jacob D.} and Joshiawa Paulk and Novak, {Jesse S.} and Kshithija Nagulapalli and Mcbrayer, {Samuel K.} and Cowley, {Glenn S.} and Javier Pineda and Jiaxi Song and Wang, {Yaoyu E.} and Carr, {Steven A.} and Root, {David E.} and Sabina Signoretti and Bradner, {James E.} and Kaelin, {William G.}",
note = "Funding Information: W.G.K. was supported by grants from the NIH (R01CA068490 and P50CA101942). A.A.C. was supported by grants from the {"}Friends of Dana-Farber{"} and the NIH [Cancer Biology Training grant T32CA009361 and the DF/HCC (Dana-Farber/Harvard Cancer Center) Kidney SPORE (Specialized Programs of Research Excellence) Career Enhancement Program award P50CA101942]. W.G.K. is a Howard Hughes Medical Institute investigator. S.K.M. was supported by the American Cancer Society Postdoctoral Fellowship award PF-14-144-01-TBE. Publisher Copyright: {\textcopyright}2017 The Authors, somerights reserved.",
year = "2017",
month = jul,
day = "12",
doi = "10.1126/scitranslmed.aal5272",
language = "English (US)",
volume = "9",
journal = "Science translational medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "398",
}