RhoA as a Mediator of Clinically Relevant Androgen Action in Prostate Cancer Cells

Recently, we have identified serum response factor (SRF) as a mediator of clinically relevant androgen receptor (AR) action in prostate cancer (PCa). Genes that rely on SRF for androgen responsiveness represent a small fraction of androgen-regulated genes, but distinguish benign from malignant prost...

Full description

Saved in:

Bibliographic Details
Published in:	Molecular endocrinology (Baltimore, Md.) Md.), 2012-05, Vol.26 (5), p.716-735
Main Authors:	Schmidt, Lucy J, Duncan, Kelly, Yadav, Neelu, Regan, Kevin M, Verone, Alissa R, Lohse, Christine M, Pop, Elena A, Attwood, Kristopher, Wilding, Gregory, Mohler, James L, Sebo, Thomas J, Tindall, Donald J, Heemers, Hannelore V
Format:	Article
Language:	eng
Subjects:	Androgens - adverse effects Androgens - pharmacology Animals Cell Nucleus - drug effects Cell Nucleus - metabolism Cell Proliferation - drug effects DNA-Binding Proteins - antagonists & inhibitors DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Gene Expression Regulation, Neoplastic - drug effects Humans LIM-Homeodomain Proteins - genetics LIM-Homeodomain Proteins - metabolism Male Mice Mice, Nude Muscle Proteins - genetics Muscle Proteins - metabolism Neoplasm Proteins - agonists Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Neoplasm Recurrence, Local Oncogene Proteins, Fusion - antagonists & inhibitors Oncogene Proteins, Fusion - genetics Oncogene Proteins, Fusion - metabolism Original Research Promoter Regions, Genetic - drug effects Prostate - drug effects Prostate - metabolism Prostate - pathology Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Prostatic Neoplasms - surgery Protein Kinase Inhibitors - pharmacology Protein Transport - drug effects Receptors, Androgen - genetics Receptors, Androgen - metabolism Recombinant Proteins - agonists Recombinant Proteins - antagonists & inhibitors Recombinant Proteins - metabolism rho-Associated Kinases - antagonists & inhibitors rho-Associated Kinases - genetics rho-Associated Kinases - metabolism rhoA GTP-Binding Protein - agonists rhoA GTP-Binding Protein - antagonists & inhibitors rhoA GTP-Binding Protein - genetics rhoA GTP-Binding Protein - metabolism Signal Transduction - drug effects Trans-Activators Transcription Factors - genetics Transcription Factors - metabolism
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Recently, we have identified serum response factor (SRF) as a mediator of clinically relevant androgen receptor (AR) action in prostate cancer (PCa). Genes that rely on SRF for androgen responsiveness represent a small fraction of androgen-regulated genes, but distinguish benign from malignant prostate, correlate with aggressive disease, and are associated with biochemical recurrence. Thus, understanding the mechanism(s) by which SRF conveys androgen regulation to its target genes may provide novel opportunities to target clinically relevant androgen signaling. Here, we show that the small GTPase ras homolog family member A (RhoA) mediates androgen-responsiveness of more than half of SRF target genes. Interference with expression of RhoA, activity of the RhoA effector Rho-associated coiled-coil containing protein kinase 1 (ROCK), and actin polymerization necessary for nuclear translocation of the SRF cofactor megakaryocytic acute leukemia (MAL) prevented full androgen regulation of SRF target genes. Androgen treatment induced RhoA activation, increased the nuclear content of MAL, and led to MAL recruitment to the promoter of the SRF target gene FHL2. In clinical specimens RhoA expression was higher in PCa cells than benign prostate cells, and elevated RhoA expression levels were associated with aggressive disease features and decreased disease-free survival after radical prostatectomy. Overexpression of RhoA markedly increased the androgen-responsiveness of select SRF target genes, in a manner that depends on its GTPase activity. The use of isogenic cell lines and a xenograft model that mimics the transition from androgen-stimulated to castration-recurrent PCa indicated that RhoA levels are not altered during disease progression, suggesting that RhoA expression levels in the primary tumor determine disease aggressiveness. Androgen-responsiveness of SRF target genes in castration-recurrent PCa cells continued to rely on AR, RhoA, SRF, and MAL and the presence of intact SRF binding sites. Silencing of RhoA, use of Rho-associated coiled-coil containing protein kinase 1 inhibitors, or an inhibitor of SRF-MAL interaction attenuated (androgen-regulated) cell viability and blunted PCa cell migration. Taken together, these studies demonstrate that the RhoA signaling axis mediates clinically relevant AR action in PCa.
ISSN:	0888-8809 1944-9917