|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Anastas, 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|
|Date Published||2019 Nov 11|
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.
|Alternate Journal||Cancer Cell|