Selective dissociation between LSD1 and GFI1B by a LSD1 inhibitor NCD38 induces the activation of ERG super-enhancer in erythroleukemia cells
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Ryusuke Yamamoto1, Masahiro Kawahara1,2, Shinji Ito3, Junko Satoh3, Goichi Tatsumi1, Masakatsu Hishizawa1, Takayoshi Suzuki4,5, and Akira Andoh2
1Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
2Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
3Medical Research Support Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
4Department of Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
5CREST, Japan Science and Technology Agency (JST), Kawaguchi, Saitama, Japan
Masahiro Kawahara, email: firstname.lastname@example.org
Keywords: LSD1; super-enhancer; GFI1B; RUNX1; leukemia
Received: September 05, 2017 Accepted: February 24, 2018 Published: April 20, 2018
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 motif of GFI1B and was actually occupied by GFI1B. NCD38 dissociated LSD1 and CoREST but not GFI1B from the ERG super-enhancer. Collectively, the selective separation of LSD1 from GFI1B by NCD38 restores the ERG super-enhancer activation and consequently upregulates ERG expression, inducing the transdifferentiation linked to the anti-leukemia effect.
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