Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Cancer cell, 2019-11, Vol.36 (5), p.528-544.e10

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •A CRISPR screen for HDAC inhibitor sensitizers in DIPG identifies KDM1A (LSD1)•Corin, a dual inhibitor of LSD1 and HDACs, inhibits DIPG growth in vitro and in vivo•Corin alters histone modifications to promote differentiation and block cell cycle•A Corin-induced gene expression signature correlates with prolonged survival in DIPG Anastas et al. show that inhibition of LSD1 sensitizes diffuse intrinsic pontine glioma (DIPG) cells to HDAC inhibition and that Corin, which inhibits both LSD1 and HDACs, potently suppresses DIPG cell growth. A Corin-induced gene expression profile correlates with improved survival of DIPG patients.