title: HDAC inhibitors target HDAC5, upregulate microRNA-125a-5p, and induce apoptosis in breast cancer cells.
abstract: Histone deacetylase inhibitors (HDACi) are novel clinical anticancer drugs that inhibit HDAC gene expression and induce cell apoptosis in human cancers. Nevertheless, the detailed mechanism or the downstream HDAC targets by which HDACi mediates apoptosis in human breast cancer cells remains unclear. Here, we show that HDACi reduce tumorigenesis and induce intrinsic apoptosis of human breast cancer cells through the microRNA miR-125a-5p in vivo and in vitro. Intrinsic apoptosis was activated by the caspase 9/3 signaling pathway. In addition, HDACi mediated the expression of miR-125a-5p by activating RUNX3/p300/HDAC5 complex. Subsequently, miR-125a-5p silenced HDAC5 post-transcriptionally in the cells treated with HDACi. Thus, a regulatory loop may exist in human breast cancer cells involving miR-125a-5p and HDAC5 that is controlled by RUNX3 signaling. Silencing of miR-125a-5p and RUNX3 inhibited cancer progression and activated apoptosis, but silencing of HDAC5 had a converse effect. In conclusion, we demonstrate a possible new mechanism by which HDACi influence tumorigenesis and apoptosis via downregulation of miR-125a-5p expression. This study provides clinical implications in cancer chemotherapy using HDACi.
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Tsung-Hua
authors.initials: TH
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Cheng-Fang
authors.initials: CF
authors.lastname: Tsai
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Long
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chin-Hu
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Deng-Chyang
authors.initials: DC
authors.lastname: Wu
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jau-Nan
authors.initials: JN
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Chang
authors.affiliation: 1] Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan [2] Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan [3] Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan [4] Center for Research Resources and Development, Kaohsiung Medical University, Kaohsiung, Taiwan [5] Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Eing-Mei
authors.initials: EM
authors.lastname: Tsai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D064593:Heterografts; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D056572:Histone Deacetylase Inhibitors; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; C404500:HDAC5 protein, human; D006655:Histone Deacetylases