Chakraborty Abhishek A, Nakamura Eijiro, Qi Jun, Creech Amanda, Jaffe Jacob D, Paulk Joshiawa, Novak Jesse S, Nagulapalli Kshithija, McBrayer Samuel K, Cowley Glenn S, Pineda Javier, Song Jiaxi, Wang Yaoyu E, Carr Steven A, Root David E, Signoretti Sabina, Bradner James E, Kaelin William G
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Sci Transl Med. 2017 Jul 12;9(398). doi: 10.1126/scitranslmed.aal5272.
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.
在最常见的肾癌——透明细胞肾细胞癌（ccRCC）中，冯·希佩尔-林道肿瘤抑制蛋白（pVHL）失活是标志性病变。pVHL缺失导致缺氧诱导因子（HIF）靶基因的转录激活，包括许多编码组蛋白赖氨酸去甲基化酶的基因。此外，染色质调节因子在这种疾病中经常发生突变。我们发现，ccRCC表现出H3K27乙酰化增加，且由于HIF依赖性的H3K27去甲基酶活性增加，导致向单甲基化或未甲基化H3K27转变。使用聚焦短发夹RNA文库以及CRISPR（成簇规律间隔短回文重复序列）/Cas9（CRISPR相关蛋白9）和一种药理抑制剂，我们发现pVHL缺陷的ccRCC细胞在生存方面高度依赖H3K27甲基转移酶EZH1。因此，靶向EZH1在ccRCC治疗中可能有用。
