Lysine-Specific Demethylase 1 Has Dual Functions as a Major Regulator of Androgen Receptor Transcriptional Activity
Changmeng Cai,
Housheng Hansen He,
Shuai Gao,
Sen Chen,
Ziyang Yu,
Yanfei Gao,
Shaoyong Chen,
Mei Wei Chen,
Jesse Zhang,
Musaddeque Ahmed,
Yang Wang,
Eric Metzger,
Roland Schüle,
X. Shirley Liu,
Myles Brown,
Steven P. Balk
Affiliations
Changmeng Cai
Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Corresponding author
Housheng Hansen He
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; Corresponding author
Shuai Gao
Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Sen Chen
Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Ziyang Yu
Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Yanfei Gao
Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Shaoyong Chen
Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Mei Wei Chen
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
Jesse Zhang
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
Musaddeque Ahmed
Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, Toronto, ON M5G1L7, Canada
Yang Wang
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
Eric Metzger
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
Roland Schüle
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
X. Shirley Liu
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
Myles Brown
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
Steven P. Balk
Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Summary: 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. : Cai et al. show that lysine-specific demethylase 1 (LSD1), although generally a transcriptional corepressor through H3K4 demethylation, functions broadly as a coactivator for androgen receptor and interacts with FOXA1 on androgen-stimulated genes. LSD1-mediated H3K4 demethylation persists at these sites, indicating a distinct coactivator function mediated by demethylation of other substrates.
