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Cancer Cell DOI:10.1016/j.ccell.2019.09.005

Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG.

Publication TypeJournal Article
Year of Publication2019
AuthorsAnastas, JN, Zee, BM, Kalin, JH, Kim, M, Guo, R, Alexandrescu, S, Blanco, MAndres, Giera, S, Gillespie, SM, Das, J, Wu, M, Nocco, S, Bonal, DM, De Nguyen, Q-, Suvà, ML, Bernstein, BE, Alani, R, Golub, TR, Cole, PA, Filbin, MG, Shi, Y
JournalCancer Cell
Volume36
Issue5
Pages528-544.e10
Date Published2019 Nov 11
ISSN1878-3686
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.

DOI10.1016/j.ccell.2019.09.005
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/31631026?dopt=Abstract

Alternate JournalCancer Cell
PubMed ID31631026