title: Chromatin reader ZMYND8 is a key target of all trans retinoic acid-mediated inhibition of cancer cell proliferation.
abstract: All trans retinoic acid (ATRA), an active vitamin-A derivative, has been shown to regulate gene expression program and thus imparts anti-proliferative activity to cancer cells. Previously, we identified a dual histone reader ZMYND8 (zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8), to be a novel target of ATRA. In the present study, we attempted to decipher the detail mechanism of its transcription regulation. ATRA can reprogram the epigenetic landscape in the upstream regulatory region of ZMYND8 thereby promoting its expression. Interestingly, there is a unique H3K27Me3 to H3K27Ac switch upon ATRA-treatment. We show here that ATRA causes dynamic changes in recruitment of transcription factor YY1 in concert with HDAC1 at ZMYND8 promoter. Further, we show that ATRA treatment triggers an anti-proliferative activity in cancer cells through regulation of ZMYND8 expression. Subsequently, in 4T1-induced syngenic tumor mouse model, ATRA injection caused significant upregulation of ZMYND8. Overall our findings highlight a novel mechanism underlying ATRA-mediated changes in ZMYND8 expression which, in turn, activates the anti-proliferative program in a cancer cell. Thus, histone reader mediated modulation of epigenetic language could play a significant role in retinoid based therapeutic strategy which is well exploited to combat tumor growth.
authors.affiliation: Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India.
authors.forename: Moitri
authors.initials: M
authors.lastname: Basu
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, India.
authors.forename: Md Wasim
authors.initials: MW
authors.lastname: Khan
authors.affiliation: Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, India.
authors.forename: Partha
authors.initials: P
authors.lastname: Chakrabarti
authors.affiliation: Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India. Electronic address: chandrima.das@saha.ac.in.
authors.forename: Chandrima
authors.initials: C
authors.lastname: Das
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D051379:Mice; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism*; D020218:Response Elements; D013997:Time Factors; D014212:Tretinoin / Q000737:chemistry / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D050986:YY1 Transcription Factor; C000617312:ZMYND8 protein, human; D014212:Tretinoin; D012319:RNA Polymerase II; D006655:Histone Deacetylases; D008239:Lysine
keywords: Cell proliferation; Chromatin reader; Gene regulation; Histone modifications; Retinoic acid; ZMYND8