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

Publication date: Available online 17 October 2019Source: Cancer CellAuthor(s): Jamie N. Anastas, Barry M. Zee, Jay H. Kalin, Mirhee Kim, Robyn Guo, Sanda Alexandrescu, Mario Andres Blanco, Stefanie Giera, Shawn M. Gillespie, Jayanta Das, Muzhou Wu, Sarah Nocco, Dennis M. Bonal, Quang-De Nguyen, Mario L. Suva, Bradley E. Bernstein, Rhoda Alani, Todd R. Golub, Philip A. Cole, Mariella G. FilbinSummaryH3K27M 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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research