title: LSD1 Substrate Binding and Gene Expression Are Affected by HDAC1-Mediated Deacetylation.
abstract: Lysine Specific Demethylase 1 (LSD1) catalyzes the demethylation of histone 3 to regulate gene expression. With a fundamental role in gene regulation, LSD1 is involved in multiple cellular processes, including embryonic development, cell proliferation, and metastasis. Significantly, LSD1 is overexpressed in multiple cancers and has emerged as a potential anticancer drug target. LSD1 is typically found in association with another epigenetic enzyme, histone deacetylase (HDAC). HDAC and LSD1 inhibitor compounds have been tested as combination anticancer agents. However, the functional link between LSD1 and HDAC has yet to be understood in detail. Here, we used a substrate trapping strategy to identify cellular substrates of HDAC1. Using inactive HDAC1 mutants, we identified LSD1 as an HDAC1 substrate. HDAC1 mediated deacetylation of LSD1 at K374 in the substrate binding lobe, which affected the histone 3 binding and gene expression activity of LSD1. The mechanistic link between HDAC1 and LSD1 established here suggests that HDAC inhibitors influence LSD1 activity, which will ultimately guide drug design targeting epigenetic enzymes.
authors.affiliation: Department of Chemistry, Wayne State University , 5101 Cass Avenue, Detroit, Michigan 48202, United States.
authors.forename: Dhanusha A
authors.initials: DA
authors.lastname: Nalawansha
authors.affiliation: Department of Chemistry, Wayne State University , 5101 Cass Avenue, Detroit, Michigan 48202, United States.
authors.forename: Mary Kay H
authors.identifier: 0000-0002-1396-3194
authors.initials: MK
authors.lastname: Pflum
mesh_terms: D000107:Acetylation; D015870:Gene Expression; D057809:HEK293 Cells; D006367:HeLa Cells; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008239:Lysine / Q000737:chemistry; D061986:MCF-7 Cells; D008745:Methylation; D008956:Models, Chemical; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; C553587:tubastatin A; D000077337:Vorinostat; D056466:Histone Demethylases; C495195:KDM1A protein, human; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D008239:Lysine