Hic-5 influences genomic and non-genomic actions of the androgen receptor in prostate myofibroblasts.
There is extensive knowledge of androgen receptor (AR) signaling in cancer cells, but less regarding androgen action in stromal cells of the tumor microenvironment. We report here the genome-wide effects of a stromal cell specific molecular adapter and AR coregulator, hydrogen peroxide-inducible gene 5 (Hic-5/TGFB1I1), on AR function in prostate myofibroblasts. Following androgen stimulation, Hic-5 rapidly translocates to the nucleus, coincident with increased phosphorylation of focal adhesion kinase. As a coregulator, Hic-5 acted to amplify or inhibit regulation of approximately 50% of AR target genes, affected androgen regulation of growth, cell adhesion, motility and invasion. These data suggest Hic-5 as a transferable adaptor between focal adhesions and the nucleus of prostate myofibroblasts, where it acts a key mediator of the specificity and sensitivity of AR signaling. We propose a model in which Hic-5 coordinates AR signaling with adhesion and extracellular matrix contacts to regulate cell behavior in the tumor microenvironment.
Cancer Biology Group, The Basil Hetzel Institute for Translational Health Research, School of Medicine, University of Adelaide, SA, Australia.
Damien A
DA
Leach
Cancer Biology Group, The Basil Hetzel Institute for Translational Health Research, School of Medicine, University of Adelaide, SA, Australia.
Eleanor F
EF
Need
Cancer Biology Group, The Basil Hetzel Institute for Translational Health Research, School of Medicine, University of Adelaide, SA, Australia.
Andrew P
AP
Trotta
School of Medicine, Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA, USA.
Melanie J
MJ
Grubisha
School of Medicine, Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA, USA.
Donald B
DB
DeFranco
Cancer Biology Group, The Basil Hetzel Institute for Translational Health Research, School of Medicine, University of Adelaide, SA, Australia. Electronic address: grant.buchanan@adelaide.edu.au.
Grant
G
Buchanan
D000728:Androgens / Q000494:pharmacology; D002448:Cell Adhesion; D002461:Cell Line, Transformed; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D060588:LIM Domain Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D058977:Molecular Sequence Annotation; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology; D059016:Tumor Microenvironment
C410798:AR protein, human; D000728:Androgens; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D011944:Receptors, Androgen; C490351:TGFB1I1 protein, human; D013739:Testosterone; D051416:Focal Adhesion Protein-Tyrosine Kinases
Androgen receptor; Fibroblasts; Focal adhesions; Microenvironment; Prostate cancer; Stroma