Cancer cell · 2019
Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Anastas Jamie N, Zee Barry M, Kalin Jay H, Kim Mirhee, Guo Robyn, Alexandrescu Sanda, Blanco Mario Andres, Giera Stefanie, Gillespie Shawn M, Das Jayanta, Wu Muzhou, Nocco Sarah, Bonal Dennis M, Nguyen Quang-De, Suva Mario L, Bernstein Bradley E, Alani Rhoda, Golub Todd R, Cole Philip A, Filbin Mariella G, Shi Yang
Аннотация
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.
Предметные рубрики MeSH
AnimalsAntineoplastic AgentsBrain Stem NeoplasmsCell DifferentiationCell Line, TumorChromatinDNA MethylationEpigenesis, GeneticFemaleGene Expression Regulation, NeoplasticGene Knockdown TechniquesGliomaHistone CodeHistone Deacetylase InhibitorsHistone DeacetylasesHistone DemethylasesHistonesHumansMiceMutationPonsRNA-SeqXenograft Model Antitumor Assays