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

被引：38

作者：

Chakraborty, Abhishek A. ^{[1
,2
]}

Nakamura, Eijiro ^{[1
,2
,8
]}

Qi, Jun ^{[1
,2
]}

Creech, Amanda ^{[3
]}

Jaffe, Jacob D. ^{[3
]}

Paulk, Joshiawa ^{[1
,2
]}

Novak, Jesse S. ^{[1
,4
]}

Nagulapalli, Kshithija ^{[5
]}

McBrayer, Samuel K. ^{[1
,2
]}

Cowley, Glenn S. ^{[3
]}

Pineda, Javier ^{[1
,2
,9
]}

Song, Jiaxi ^{[1
,2
,4
]}

Wang, Yaoyu E. ^{[5
]}

Carr, Steven A. ^{[3
]}

Root, David E. ^{[3
]}

Signoretti, Sabina ^{[1
,2
,4
]}

Bradner, James E. ^{[1
,2
]}

Kaelin, William G., Jr. ^{[1
,2
,3
,6
,7
]}

机构：

[1] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[2] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02215 USA

[3] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA

[4] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[5] Harvard Med Sch, Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02215 USA

[6] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[7] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[8] Kyoto Univ, Med Innovat Ctr, DSK Project, Grad Sch Med, Kyoto 6068397, Japan

[9] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2017年 / 9卷 / 398期

关键词：

RENAL-CELL CARCINOMA; ACUTE LYMPHOBLASTIC-LEUKEMIA; EXPRESSION PROFILES; GENE-EXPRESSION; KIDNEY CANCER; BCR-ABL; DEMETHYLASE; HYPOXIA; CHROMATIN; REVEALS;

D O I：

10.1126/scitranslmed.aal5272

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页数：14

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