title: Lysine-specific demethylase 1 has dual functions as a major regulator of androgen receptor transcriptional activity.
abstract: Lysine-Specific Demethylase 1 (LSD1, KDM1A) functions as a transcriptional corepressor through demethylation of histone 3 lysine 4 (H3K4) but has a coactivator function on some genes through mechanisms that are unclear. We show that LSD1, interacting with CoREST, associates with and coactivates androgen receptor (AR) on a large fraction of androgen-stimulated genes. A subset of these AR/LSD1-associated enhancer sites have histone 3 threonine 6 phosphorylation (H3T6ph), and these sites are further enriched for androgen-stimulated genes. Significantly, despite its coactivator activity, LSD1 still mediates H3K4me2 demethylation at these androgen-stimulated enhancers. FOXA1 is also associated with LSD1 at AR-regulated enhancer sites, and a FOXA1 interaction with LSD1 enhances binding of both proteins at these sites. These findings show that LSD1 functions broadly as a regulator of AR function, that it maintains a transcriptional repression function at AR-regulated enhancers through H3K4 demethylation, and that it has a distinct AR-linked coactivator function mediated by demethylation of other substrates.
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. Electronic address: ccai1@bidmc.harvard.edu.
authors.forename: Changmeng
authors.initials: C
authors.lastname: Cai
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA; Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, Toronto, ON M5G1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G2M9, Canada. Electronic address: hansenhe@uhnresearch.ca.
authors.forename: Housheng Hansen
authors.initials: HH
authors.lastname: He
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Gao
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sen
authors.initials: S
authors.lastname: Chen
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Ziyang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Shaoyong
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mei Wei
authors.initials: MW
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, Toronto, ON M5G1L7, Canada.
authors.forename: Musaddeque
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, and BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University and Deutsche Konsortium für Translationale Krebsforschung (DKTK), Standort Freiburg, 79106 Freiburg, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Metzger
authors.affiliation: Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, and BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University and Deutsche Konsortium für Translationale Krebsforschung (DKTK), Standort Freiburg, 79106 Freiburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D016384:Consensus Sequence; D004742:Enhancer Elements, Genetic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D056466:Histone Demethylases / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D011499:Protein Processing, Post-Translational; D011944:Receptors, Androgen / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; D011944:Receptors, Androgen; D056466:Histone Demethylases; C495195:KDM1A protein, human