title: Negative regulation of ERα by a novel protein CAC1 through association with histone demethylase LSD1.
abstract: ERα, a critical transcriptional factor for breast cancer proliferation, is regulated by a complex binding repertoire that includes coactivators and corepressors. Here, we identified a novel class of ERα coregulator called CAC1. The CoRNR box of CAC1 was required for the binding to and inactivation of ERα. CAC1 also associated with histone demethylase LSD1 and suppressed LSD1-enhanced ERα activity. CAC1 impaired recruitment of ERα and LSD1 to the ERα-responsive promoter, leading to greater H3K9me3 accumulation. This effect was reversed by CAC1 depletion. Finally, CAC1 increased paclitaxel-induced cell death in ERα-positive MCF7 cells, which are paclitaxel-resistant. Overall, our study provides the first evidence that CAC1, associated with LSD1, functions as an ERα corepressor, implicating a potential antitumor target in ERα-positive breast cancer.
authors.affiliation: Department of Molecular Biology, BK21 Graduate Program, Dankook University, Yongin-si, Gyeonggi-do 448-701, Republic of Korea.
authors.forename: JuHyun
authors.initials: J
authors.lastname: Kim
authors.forename: Ui-Hyun
authors.initials: UH
authors.lastname: Park
authors.forename: MinO
authors.initials: M
authors.lastname: Moon
authors.forename: Soo-Jong
authors.initials: SJ
authors.lastname: Um
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D044842:Cullin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D006656:Protamine Kinase / Q000378:metabolism; D034622:RNA Interference; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C546534:CACUL1 protein, human; D056970:Co-Repressor Proteins; D044842:Cullin Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D006657:Histones; D050505:Mutant Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D056466:Histone Demethylases; C495195:KDM1A protein, human; D006656:Protamine Kinase; D017239:Paclitaxel