title: Trichostatin A enhances estrogen receptor-alpha repression in MCF-7 breast cancer cells under hypoxia.
abstract: Estrogen receptor (ER) is a crucial determinant of resistance to endocrine therapy, which may change during the progression of breast cancer. We previously showed that hypoxia induces ESR1 gene repression and ERα protein degradation via proteasome-mediated pathway in breast cancer cells. HDAC plays important roles in the regulation of histone and non-histone protein post-translational modification. HDAC inhibitors can induce epigenetic changes and have therapeutic potential for targeting various cancers. Trichostatin A exerts potent antitumor activities against breast cancer cells in vitro and in vivo. In this report, we show that TSA augments ESR1 gene repression at the transcriptional level and downregulates ERα protein expression under hypoxic conditions through a proteasome-mediated pathway. TSA-induced estrogen response element-driven reporter activity in the absence of estrogen was synergistically enhanced under hypoxia; however, TSA inhibited cell proliferation under both normoxia and hypoxia. Our data show that the hypoxia-induced repression of ESR1 and degradation of ERα are enhanced by concomitant treatment with TSA. These findings expand our understanding of hormone responsiveness in the tumor microenvironment; however, additional in-depth studies are required to elucidate the detailed mechanisms of TSA-induced ERα regulation under hypoxia.
authors.affiliation: Department of Integrated Bioscience and Biotechnology, College of Life Science, Sejong University, Kwangjingu, Kunjadong, Seoul 143-747, Republic of Korea.
authors.forename: Hyunggyun
authors.initials: H
authors.lastname: Noh
authors.affiliation: Department of Integrated Bioscience and Biotechnology, College of Life Science, Sejong University, Kwangjingu, Kunjadong, Seoul 143-747, Republic of Korea.
authors.forename: Joonwoo
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Integrated Bioscience and Biotechnology, College of Life Science, Sejong University, Kwangjingu, Kunjadong, Seoul 143-747, Republic of Korea.
authors.forename: Myeongguk
authors.initials: M
authors.lastname: Shim
authors.affiliation: Department of Integrated Bioscience and Biotechnology, College of Life Science, Sejong University, Kwangjingu, Kunjadong, Seoul 143-747, Republic of Korea. Electronic address: yjlee@sejong.ac.kr.
authors.forename: YoungJoo
authors.initials: Y
authors.lastname: Lee
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D061986:MCF-7 Cells; D010100:Oxygen / Q000378:metabolism*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D006877:Hydroxamic Acids; C012589:trichostatin A; D010100:Oxygen
keywords: Breast cancer; Estrogen receptor; Hypoxia; Trichostatin A