Selective dissociation between LSD1 and GFI1B by a LSD1 inhibitor NCD38 induces the activation of ERG super-enhancer in erythroleukemia cells

Oncotarget
Ryusuke YamamotoA Andoh

Abstract

Lysine-specific demethylase 1 (LSD1) is a histone modifier for transcriptional repression involved in the regulation of hematopoiesis. We previously reported that a LSD1 inhibitor NCD38 induces transdifferentiation from erythroid lineage to granulomonocytic lineage and exerts anti-leukemia effect through de-repression of the specific super-enhancers of hematopoietic regulators including ERG in a human erythroleukemia cell line, HEL. However, the mechanistic basis for this specificity of NCD38 has remained unclear. Herein, we report major partners associated with LSD1 and clarify the mechanism in HEL cells. Proteome analysis identified 54 candidate proteins associated with LSD1, including several transcription factors such as GFI1B and RUNX1 as well as BRAF-histone deacetylase complex (BHC) components such as CoREST, HDAC1, and HDAC2. NCD38 selectively disrupted the interaction of LSD1 with GFI1B but not with RUNX1, CoREST, HDAC1 and HDAC2. Erg was downregulated in murine erythroid progenitors with prominent upregulation of Gfi1b. NCD38 induced ERG and attenuated an erythroid marker CD235a in HEL while this attenuation was mimicked by the lentiviral overexpression of ERG. The ERG super-enhancer contained the conserved binding mo...Continue Reading

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Nov 24, 2018·Clinical Epigenetics·Elias Orouji, Jochen Utikal
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Datasets Mentioned

BETA
BC040168
GSE59859
GSM1448833
GSE36030

Methods Mentioned

BETA
co-immunoprecipitation
co-IP
FACS
immunoprecipitation
ChIP-seq
PCR

Software Mentioned

Progenesis QI
ECR
Integrative Genomics Viewer ( IGV )
Pro Group
ECR browser
ProteinPilot

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