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Cell Rep. 2014 Dec 11;9(5):1618-1627. doi: 10.1016/j.celrep.2014.11.008. Epub 2014 Dec 4.

Lysine-specific demethylase 1 has dual functions as a major regulator of androgen receptor transcriptional activity.

Author information

1
Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. Electronic address: ccai1@bidmc.harvard.edu.
2
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.
3
Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
4
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
5
Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, Toronto, ON M5G1L7, Canada.
6
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.
7
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.
8
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.
9
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.

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.

PMID:
25482560
PMCID:
PMC4268354
DOI:
10.1016/j.celrep.2014.11.008
[Indexed for MEDLINE]
Free PMC Article

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