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

被引：133

作者：

Anastas, Jamie N. ^{[1
,2
,3
]}

Zee, Barry M. ^{[1
,2
,3
]}

Kalin, Jay H. ^{[4
,5
]}

Kim, Mirhee ^{[6
]}

Guo, Robyn ^{[7
]}

Alexandrescu, Sanda ^{[8
,9
,10
]}

Blanco, Mario Andres ^{[11
]}

Giera, Stefanie ^{[12
]}

Gillespie, Shawn M. ^{[13
,14
,15
]}

Das, Jayanta ^{[16
]}

Wu, Muzhou ^{[17
]}

Nocco, Sarah ^{[17
]}

Bonal, Dennis M. ^{[18
]}

Quang-De Nguyen ^{[18
]}

Suva, Mario L. ^{[13
,14
,15
,19
]}

Bernstein, Bradley E. ^{[13
,14
,15
,19
]}

Alani, Rhoda ^{[17
]}

Golub, Todd R. ^{[19
,20
,21
]}

Cole, Philip A. ^{[4
,5
]}

Filbin, Mariella G. ^{[9
,10
,19
]}

Shi, Yang ^{[1
,2
,3
]}

机构：

[1] Boston Childrens Hosp, Dept Med, Div Newborn Med, Boston, MA 02115 USA

[2] Boston Childrens Hosp, Dept Med, Epigenet Program, Boston, MA 02115 USA

[3] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA

[4] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA

[6] NYU, Med Sch, New York, NY 10016 USA

[7] Duke Univ, Durham, NC 27708 USA

[8] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA

[9] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA

[10] Childrens Hosp Canc Ctr, Boston, MA 02215 USA

[11] Univ Penn, Sch Vet Med, Dept Biomed Sci, Philadelphia, PA 19104 USA

[12] Sanofi, Cambridge, MA 02139 USA

[13] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[14] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA

[15] Harvard Med Sch, Boston, MA 02114 USA

[16] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA

[17] Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02118 USA

[18] Dana Farber Canc Inst, Ctr Biomed Imaging Oncol, Lurie Family Imaging Ctr, Boston, MA 02215 USA

[19] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[20] MIT, Koch Inst Integrat Canc Res, 500 Main St, Cambridge, MA 02142 USA

[21] Howard Hughes Med Inst, 4000 Jones Bridge Rd, Chevy Chase, MD 20815 USA

来源：

CANCER CELL | 2019年 / 36卷 / 05期

关键词：

HISTONE DEACETYLASE INHIBITOR; DNA HYPOMETHYLATION; GENE-EXPRESSION; LSD1; DEMETHYLASE; CELLS; MUTATION; EZH2; GLIOBLASTOMA; METHYLATION;

D O I：

10.1016/j.ccell.2019.09.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：528 / +

页数：27

共 45 条

[1] RE-PROGRAMING CHROMATIN WITH A BIFUNCTIONAL LSD1/HDAC INHIBITOR INDUCES THERAPEUTIC DIFFERENTIATION IN DIPG
Anastas, Jamie
Filbin, Mariella
Kim, Mirhee
Kalin, Jay
Zee, Barry
Blanco, Andres
Das, Jayanta
Golub, Todd
Cole, Philip
Shi, Yang
NEURO-ONCOLOGY, 2018, 20 : 107 - 108
[2] LSD1 inhibition induces differentiation in murine models of AML
Barth, J.
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Oncology Research and Treatment, 2015, 38 : 46 - 47
[3] Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer
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[4] Dual HDAC and LSD1 inhibition as a novel strategy to overcome BRAF inhibitor resistance
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[5] LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma
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[7] Concomitant epigenetic targeting of LSD1 and HDAC synergistically induces mitochondrial apoptosis in rhabdomyosarcoma cells
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[8] Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells
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[10] Installation of Pargyline, a LSD1 Inhibitor, in the HDAC Inhibitory Template Culminated in the Identification of a Tractable Antiprostate Cancer Agent
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