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

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Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG.
Cancer Cell ( IF 48.8 ) Pub Date : 2019-10-17 , DOI: 10.1016/j.ccell.2019.09.005
Jamie N Anastas ₁ , Barry M Zee ₁ , Jay H Kalin ₂ , Mirhee Kim ₃ , Robyn Guo ₄ , Sanda Alexandrescu ₅ , Mario Andres Blanco ₆ , Stefanie Giera ₇ , Shawn M Gillespie ₈ , Jayanta Das ₉ , Muzhou Wu ₁₀ , Sarah Nocco ₁₀ , Dennis M Bonal ₁₁ , Quang-De Nguyen ₁₁ , Mario L Suva ₁₂ , Bradley E Bernstein ₁₂ , Rhoda Alani ₁₀ , Todd R Golub ₁₃ , Philip A Cole ₂ , Mariella G Filbin ₁₄ , Yang Shi ₁

Affiliation

Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Department of Medicine, Brigham and Womens Hospital, Boston, MA 02115, USA.
NYU Medical School, New York, NY 10016, USA.
Duke University, Durham, NC 27708, USA.
Department of Pathology Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Cancer Center, Boston, MA 02215, USA.
Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sanofi, Cambridge, MA 02139, USA.
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Eshelman School of Pharmacy, UNC Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA.
Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, 20815 MD, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Cancer Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

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.

中文翻译：

用双功能LSD1 / HDAC抑制剂重编程染色质可诱导DIPG的治疗分化。

H3K27M突变导致表观遗传功能障碍，经常在弥漫性桥脑神经胶质瘤（DIPG）（一种无法治愈的小儿癌症）中观察到。我们进行了CRISPR筛选，揭示了敲除编码赖氨酸特异性脱甲基酶1（LSD1）的KDM1A使DIPG细胞对组蛋白脱乙酰基酶（HDAC）抑制剂敏感。一致地，Corin是HDAC和LSD1的双功能抑制剂，在体外和异种移植物中均能有效抑制DIPG的生长。从机制上讲，Corin会增加由H3K27M组蛋白抑制的H3K27me3水平，并同时增加分化相关基因的HDAC靶向H3K27ac和LSD1靶向H3K4me1。Corin治疗会诱导细胞死亡，细胞周期停滞和细胞分化表型，并驱动与DIPG患者存活时间增加相关的转录变化。

更新日期：2019-11-09

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