title: Scaffold attachment factor B1 regulates the androgen receptor in concert with the growth inhibitory kinase MST1 and the methyltransferase EZH2.
abstract: The androgen receptor (AR) is a transcription factor that employs many diverse interactions with coregulatory proteins in normal physiology and in prostate cancer (PCa). The AR mediates cellular responses in association with chromatin complexes and kinase cascades. Here we report that the nuclear matrix protein, scaffold attachment factor B1 (SAFB1), regulates AR activity and AR levels in a manner that suggests its involvement in PCa. SAFB1 mRNA expression was lower in PCa in comparison with normal prostate tissue in a majority of publicly available RNA expression data sets. SAFB1 protein levels were also reduced with disease progression in a cohort of human PCa that included metastatic tumors. SAFB1 bound to AR and was phosphorylated by the MST1 (Hippo homolog) serine-threonine kinase, previously shown to be an AR repressor, and MST1 localization to AR-dependent promoters was inhibited by SAFB1 depletion. Knockdown of SAFB1 in androgen-dependent LNCaP PCa cells increased AR and prostate-specific antigen (PSA) levels, stimulated growth of cultured cells and subcutaneous xenografts and promoted a more aggressive phenotype, consistent with a repressive AR regulatory function. SAFB1 formed a complex with the histone methyltransferase EZH2 at AR-interacting chromatin sites in association with other polycomb repressive complex 2 (PRC2) proteins. We conclude that SAFB1 acts as a novel AR co-regulator at gene loci where signals from the MST1/Hippo and EZH2 pathways converge.
authors.affiliation: Cancer Biology Program, Departments of Surgery, Medicine and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: N K
authors.initials: NK
authors.lastname: Mukhopadhyay
authors.affiliation: 1] Cancer Biology Program, Departments of Surgery, Medicine and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA [2] Department of Surgery, Urological Diseases Research Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.affiliation: Cancer Biology Program, Departments of Surgery, Medicine and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: You
authors.affiliation: Cancer Biology Program, Departments of Surgery, Medicine and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Morello
authors.affiliation: Department of Surgery, Urological Diseases Research Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Hager
authors.affiliation: Cancer Biology Program, Departments of Surgery, Medicine and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: W-C
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Department of Surgery, Urological Diseases Research Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ramachandran
authors.affiliation: Cancer Biology Program, Departments of Surgery, Medicine and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Cancer Biology Program, Departments of Surgery, Medicine and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Cinar
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical Centre, New York, NY, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Rubin
authors.affiliation: Department of Surgery, Urological Diseases Research Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Adam
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Oesterreich
authors.affiliation: 1] Cancer Biology Program, Departments of Surgery, Medicine and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA [2] Department of Surgery, Urological Diseases Research Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Di Vizio
authors.affiliation: 1] Cancer Biology Program, Departments of Surgery, Medicine and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA [2] Department of Surgery, Urological Diseases Research Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Freeman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D036961:Matrix Attachment Region Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C410798:AR protein, human; D006657:Histones; D036961:Matrix Attachment Region Binding Proteins; D034521:Nuclear Matrix-Associated Proteins; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; C109132:SAFB protein, human; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D000076983:Histone Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D017430:Prostate-Specific Antigen
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