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

摘要: // Ryusuke Yamamoto 1 , Masahiro Kawahara 1, 2 Shinji Ito 3 Junko Satoh Goichi Tatsumi Masakatsu Hishizawa Takayoshi Suzuki 4, 5 and Akira Andoh Department of Hematology Oncology, Graduate School Medicine, Kyoto University, Kyoto, Japan Shiga University Medical Science, Otsu, Shiga, Research Support Center, 4 Chemistry, Prefectural CREST, Science Technology Agency (JST), Kawaguchi, Saitama, Correspondence to: Kawahara, email: mkawahar@belle.shiga-med.ac.jp Keywords: LSD1; super-enhancer; GFI1B; RUNX1; leukemia Received: September 05, 2017      Accepted: February 24, 2018      Published: April 20, 2018 ABSTRACT Lysine-specific demethylase (LSD1) is a histone modifier for transcriptional repression involved in the regulation hematopoiesis. We previously reported that LSD1 inhibitor NCD38 induces transdifferentiation from erythroid lineage to granulomonocytic exerts anti-leukemia effect through de-repression specific super-enhancers hematopoietic regulators including ERG human erythroleukemia cell line, HEL. However, mechanistic basis this specificity has remained unclear. Herein, we report major partners associated with clarify mechanism HEL cells. Proteome analysis identified 54 candidate proteins LSD1, several transcription factors such as GFI1B RUNX1 well BRAF-histone deacetylase complex (BHC) components CoREST, HDAC1, HDAC2. selectively disrupted interaction but not RUNX1, HDAC1 Erg was downregulated murine progenitors prominent upregulation Gfi1b . induced attenuated an marker CD235a while attenuation mimicked by lentiviral overexpression ERG. The super-enhancer contained conserved binding motif actually occupied GFI1B. dissociated CoREST super-enhancer. Collectively, selective separation restores activation consequently upregulates expression, inducing linked effect.