| Literature DB >> 31631026 |
Jamie N Anastas1, Barry M Zee1, Jay H Kalin2, Mirhee Kim3, Robyn Guo4, Sanda Alexandrescu5, Mario Andres Blanco6, Stefanie Giera7, Shawn M Gillespie8, Jayanta Das9, Muzhou Wu10, Sarah Nocco10, Dennis M Bonal11, Quang-De Nguyen11, Mario L Suva12, Bradley E Bernstein12, Rhoda Alani10, Todd R Golub13, Philip A Cole2, Mariella G Filbin14, Yang Shi15.
Abstract
H3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetylase (HDAC) inhibitors. Consistently, Corin, a bifunctional inhibitor of HDACs and LSD1, potently inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin increases H3K27me3 levels suppressed by H3K27M histones, and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at differentiation-associated genes. Corin treatment induces cell death, cell-cycle arrest, and a cellular differentiation phenotype and drives transcriptional changes correlating with increased survival time in DIPG patients. These data suggest a strategy for treating DIPG by simultaneously inhibiting LSD1 and HDACs.Entities:
Keywords: CRISPR screen; DIPG; HDAC; Histone H3 K27M; LSD1; cancer stem cell; differentiation therapy; enhancer; epigenetic; glioma
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Year: 2019 PMID： 31631026 DOI： 10.1016/j.ccell.2019.09.005
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743