title: Identification of a Novel Coregulator, SH3YL1, That Interacts With the Androgen Receptor N-Terminus.
abstract: Nuclear receptor (NR)-mediated transcriptional activity is a dynamic process that is regulated by the binding of ligands that induce distinct conformational changes in the NR. These structural alterations lead to the differential recruitment of coregulators (coactivators or corepressors) that control the expression of NR-regulated genes. Here, we show that a stretch of proline residues located within the N-terminus of androgen receptor (AR) is a bona fide coregulator binding surface, the disruption of which reduces the androgen-dependent proliferation and migration of prostate cancer (PCa) cells. Using T7 phage display, we identified a novel AR-interacting protein, Src homology 3 (SH3)-domain containing, Ysc84-like 1 (SH3YL1), whose interaction with the receptor is dependent upon this polyproline domain. As with mutations within the AR polyproline domain, knockdown of SH3YL1 attenuated androgen-mediated cell growth and migration. RNA expression analysis revealed that SH3YL1 was required for the induction of a subset of AR-modulated genes. Notable was the observation that ubinuclein 1 (UBN1), a key member of a histone H3.3 chaperone complex, was a transcriptional target of the AR/SH3YL1 complex, correlated with aggressive PCa in patients, and was necessary for the maximal androgen-mediated proliferation and migration of PCa cells. Collectively, these data highlight the importance of an amino-terminal activation domain, its associated coregulator, and downstream transcriptional targets in regulating cellular processes of pathological importance in PCa.
authors: Center for Nuclear Receptors and Cell Signaling (A.M.B., Y.S., D.E.F.), Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204; R&D Compliance (S.G.), Grifols Therapeutics Inc, Research Triangle Park, North Carolina 27709; Department of Pharmacology and Cancer Biology (S.G., D.P.M.), Duke University School of Medicine, Durham, North Carolina 27710; Department of Molecular and Cellular Biology (K.R., C.C.), Baylor College of Medicine, Houston, Texas 77030; Cancer Biology and Pharmacology (Y.Y.S., E.C.), Genome Institute of Singapore, A*STAR, Singapore 138672; Department of Clinical Cancer Prevention (L.R.B.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030; Faculty of Health Sciences (E.C.), University of Macau, Taipa, Macau, China, 9999078; Department of Integrative Biology and Pharmacology (J.T.C.), School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030; and Genomic Medicine Program (D.E.F.), The Houston Methodist Research Institute, Houston, Texas 77030.
authors: Alicia M
authors: AM
authors: Blessing
authors: Center for Nuclear Receptors and Cell Signaling (A.M.B., Y.S., D.E.F.), Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204; R&D Compliance (S.G.), Grifols Therapeutics Inc, Research Triangle Park, North Carolina 27709; Department of Pharmacology and Cancer Biology (S.G., D.P.M.), Duke University School of Medicine, Durham, North Carolina 27710; Department of Molecular and Cellular Biology (K.R., C.C.), Baylor College of Medicine, Houston, Texas 77030; Cancer Biology and Pharmacology (Y.Y.S., E.C.), Genome Institute of Singapore, A*STAR, Singapore 138672; Department of Clinical Cancer Prevention (L.R.B.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030; Faculty of Health Sciences (E.C.), University of Macau, Taipa, Macau, China, 9999078; Department of Integrative Biology and Pharmacology (J.T.C.), School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030; and Genomic Medicine Program (D.E.F.), The Houston Methodist Research Institute, Houston, Texas 77030.
authors: Sathya
authors: S
authors: Ganesan
authors: Center for Nuclear Receptors and Cell Signaling (A.M.B., Y.S., D.E.F.), Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204; R&D Compliance (S.G.), Grifols Therapeutics Inc, Research Triangle Park, North Carolina 27709; Department of Pharmacology and Cancer Biology (S.G., D.P.M.), Duke University School of Medicine, Durham, North Carolina 27710; Department of Molecular and Cellular Biology (K.R., C.C.), Baylor College of Medicine, Houston, Texas 77030; Cancer Biology and Pharmacology (Y.Y.S., E.C.), Genome Institute of Singapore, A*STAR, Singapore 138672; Department of Clinical Cancer Prevention (L.R.B.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030; Faculty of Health Sciences (E.C.), University of Macau, Taipa, Macau, China, 9999078; Department of Integrative Biology and Pharmacology (J.T.C.), School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030; and Genomic Medicine Program (D.E.F.), The Houston Methodist Research Institute, Houston, Texas 77030.
authors: Kimal
authors: K
authors: Rajapakshe
authors: Center for Nuclear Receptors and Cell Signaling (A.M.B., Y.S., D.E.F.), Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204; R&D Compliance (S.G.), Grifols Therapeutics Inc, Research Triangle Park, North Carolina 27709; Department of Pharmacology and Cancer Biology (S.G., D.P.M.), Duke University School of Medicine, Durham, North Carolina 27710; Department of Molecular and Cellular Biology (K.R., C.C.), Baylor College of Medicine, Houston, Texas 77030; Cancer Biology and Pharmacology (Y.Y.S., E.C.), Genome Institute of Singapore, A*STAR, Singapore 138672; Department of Clinical Cancer Prevention (L.R.B.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030; Faculty of Health Sciences (E.C.), University of Macau, Taipa, Macau, China, 9999078; Department of Integrative Biology and Pharmacology (J.T.C.), School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030; and Genomic Medicine Program (D.E.F.), The Houston Methodist Research Institute, Houston, Texas 77030.
authors: Ying
authors: Y
authors: Ying Sung
authors: Center for Nuclear Receptors and Cell Signaling (A.M.B., Y.S., D.E.F.), Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204; R&D Compliance (S.G.), Grifols Therapeutics Inc, Research Triangle Park, North Carolina 27709; Department of Pharmacology and Cancer Biology (S.G., D.P.M.), Duke University School of Medicine, Durham, North Carolina 27710; Department of Molecular and Cellular Biology (K.R., C.C.), Baylor College of Medicine, Houston, Texas 77030; Cancer Biology and Pharmacology (Y.Y.S., E.C.), Genome Institute of Singapore, A*STAR, Singapore 138672; Department of Clinical Cancer Prevention (L.R.B.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030; Faculty of Health Sciences (E.C.), University of Macau, Taipa, Macau, China, 9999078; Department of Integrative Biology and Pharmacology (J.T.C.), School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030; and Genomic Medicine Program (D.E.F.), The Houston Methodist Research Institute, Houston, Texas 77030.
authors: Lakshmi
authors: L
authors: Reddy Bollu
authors: Center for Nuclear Receptors and Cell Signaling (A.M.B., Y.S., D.E.F.), Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204; R&D Compliance (S.G.), Grifols Therapeutics Inc, Research Triangle Park, North Carolina 27709; Department of Pharmacology and Cancer Biology (S.G., D.P.M.), Duke University School of Medicine, Durham, North Carolina 27710; Department of Molecular and Cellular Biology (K.R., C.C.), Baylor College of Medicine, Houston, Texas 77030; Cancer Biology and Pharmacology (Y.Y.S., E.C.), Genome Institute of Singapore, A*STAR, Singapore 138672; Department of Clinical Cancer Prevention (L.R.B.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030; Faculty of Health Sciences (E.C.), University of Macau, Taipa, Macau, China, 9999078; Department of Integrative Biology and Pharmacology (J.T.C.), School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030; and Genomic Medicine Program (D.E.F.), The Houston Methodist Research Institute, Houston, Texas 77030.
authors: Yan
authors: Y
authors: Shi
authors: Center for Nuclear Receptors and Cell Signaling (A.M.B., Y.S., D.E.F.), Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204; R&D Compliance (S.G.), Grifols Therapeutics Inc, Research Triangle Park, North Carolina 27709; Department of Pharmacology and Cancer Biology (S.G., D.P.M.), Duke University School of Medicine, Durham, North Carolina 27710; Department of Molecular and Cellular Biology (K.R., C.C.), Baylor College of Medicine, Houston, Texas 77030; Cancer Biology and Pharmacology (Y.Y.S., E.C.), Genome Institute of Singapore, A*STAR, Singapore 138672; Department of Clinical Cancer Prevention (L.R.B.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030; Faculty of Health Sciences (E.C.), University of Macau, Taipa, Macau, China, 9999078; Department of Integrative Biology and Pharmacology (J.T.C.), School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030; and Genomic Medicine Program (D.E.F.), The Houston Methodist Research Institute, Houston, Texas 77030.
authors: Edwin
authors: E
authors: Cheung
authors: Center for Nuclear Receptors and Cell Signaling (A.M.B., Y.S., D.E.F.), Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204; R&D Compliance (S.G.), Grifols Therapeutics Inc, Research Triangle Park, North Carolina 27709; Department of Pharmacology and Cancer Biology (S.G., D.P.M.), Duke University School of Medicine, Durham, North Carolina 27710; Department of Molecular and Cellular Biology (K.R., C.C.), Baylor College of Medicine, Houston, Texas 77030; Cancer Biology and Pharmacology (Y.Y.S., E.C.), Genome Institute of Singapore, A*STAR, Singapore 138672; Department of Clinical Cancer Prevention (L.R.B.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030; Faculty of Health Sciences (E.C.), University of Macau, Taipa, Macau, China, 9999078; Department of Integrative Biology and Pharmacology (J.T.C.), School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030; and Genomic Medicine Program (D.E.F.), The Houston Methodist Research Institute, Houston, Texas 77030.
authors: Cristian
authors: C
authors: Coarfa
authors: Center for Nuclear Receptors and Cell Signaling (A.M.B., Y.S., D.E.F.), Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204; R&D Compliance (S.G.), Grifols Therapeutics Inc, Research Triangle Park, North Carolina 27709; Department of Pharmacology and Cancer Biology (S.G., D.P.M.), Duke University School of Medicine, Durham, North Carolina 27710; Department of Molecular and Cellular Biology (K.R., C.C.), Baylor College of Medicine, Houston, Texas 77030; Cancer Biology and Pharmacology (Y.Y.S., E.C.), Genome Institute of Singapore, A*STAR, Singapore 138672; Department of Clinical Cancer Prevention (L.R.B.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030; Faculty of Health Sciences (E.C.), University of Macau, Taipa, Macau, China, 9999078; Department of Integrative Biology and Pharmacology (J.T.C.), School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030; and Genomic Medicine Program (D.E.F.), The Houston Methodist Research Institute, Houston, Texas 77030.
authors: Jeffrey T
authors: JT
authors: Chang
authors: Center for Nuclear Receptors and Cell Signaling (A.M.B., Y.S., D.E.F.), Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204; R&D Compliance (S.G.), Grifols Therapeutics Inc, Research Triangle Park, North Carolina 27709; Department of Pharmacology and Cancer Biology (S.G., D.P.M.), Duke University School of Medicine, Durham, North Carolina 27710; Department of Molecular and Cellular Biology (K.R., C.C.), Baylor College of Medicine, Houston, Texas 77030; Cancer Biology and Pharmacology (Y.Y.S., E.C.), Genome Institute of Singapore, A*STAR, Singapore 138672; Department of Clinical Cancer Prevention (L.R.B.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030; Faculty of Health Sciences (E.C.), University of Macau, Taipa, Macau, China, 9999078; Department of Integrative Biology and Pharmacology (J.T.C.), School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030; and Genomic Medicine Program (D.E.F.), The Houston Methodist Research Institute, Houston, Texas 77030.
authors: Donald P
authors: DP
authors: McDonnell
authors: Center for Nuclear Receptors and Cell Signaling (A.M.B., Y.S., D.E.F.), Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204; R&D Compliance (S.G.), Grifols Therapeutics Inc, Research Triangle Park, North Carolina 27709; Department of Pharmacology and Cancer Biology (S.G., D.P.M.), Duke University School of Medicine, Durham, North Carolina 27710; Department of Molecular and Cellular Biology (K.R., C.C.), Baylor College of Medicine, Houston, Texas 77030; Cancer Biology and Pharmacology (Y.Y.S., E.C.), Genome Institute of Singapore, A*STAR, Singapore 138672; Department of Clinical Cancer Prevention (L.R.B.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030; Faculty of Health Sciences (E.C.), University of Macau, Taipa, Macau, China, 9999078; Department of Integrative Biology and Pharmacology (J.T.C.), School of Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030; and Genomic Medicine Program (D.E.F.), The Houston Methodist Research Institute, Houston, Texas 77030.
authors: Daniel E
authors: DE
authors: Frigo
mesh_terms: D000728:Androgens / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C410798:AR protein, human; D000728:Androgens; D002352:Carrier Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011944:Receptors, Androgen; C560582:SH3YL1 protein, human; D014157:Transcription Factors; C406814:UBN1 protein, human; C011083:polyproline