Alteration to the expression and activity of androgen receptor (AR) coregulators in prostate cancer is an important mechanism driving disease progression and therapy resistance. Using a novel proteomic technique, we identified a new AR coregulator, the transcription factor Grainyhead-like 2 (GRHL2), and demonstrated its essential role in the oncogenic AR signaling axis. GRHL2 colocalized with AR in prostate tumors and was frequently amplified and upregulated in prostate cancer. Importantly, GRHL2 maintained AR expression in multiple prostate cancer model systems, was required for cell proliferation, enhanced AR's transcriptional activity, and colocated with AR at specific sites on chromatin to regulate genes relevant to disease progression. GRHL2 is itself an AR-regulated gene, creating a positive feedback loop between the two factors. The link between GRHL2 and AR also applied to constitutively active truncated AR variants (ARV), as GRHL2 interacted with and regulated ARVs and vice versa. These oncogenic functions of GRHL2 were counterbalanced by its ability to suppress epithelial–mesenchymal transition and cell invasion. Mechanistic evidence suggested that AR assisted GRHL2 in maintaining the epithelial phenotype. In summary, this study has identified a new AR coregulator with a multifaceted role in prostate cancer, functioning as an enhancer of the oncogenic AR signaling pathway but also as a suppressor of metastasis-related phenotypes.
Bibliographical noteFunding Information:
The authors thank Drs. Colm Morrisey, Larry True, and Tony Rizzardi (University of Washington) for assistance with the prostate cancer tissue microarray, Drs. Clive D'Santos, Chris Taylor, and Eva Papachristou from the Cancer Research UK Cambridge Institute Proteomics Core Facility for expert assistance with RIME, Mark Van der Hoek from the South Australian Health and Medical Research Institute Genomics Facility for assistance with ChIP-seq and RNA-seq, and Dr. Nicholas Mitsiades (Baylor College of Medicine) for sharing unpublished data. The results published here are in part based on data generated by TCGA, established by the NCI and the National Human Genome Research Institute, and we are grateful to the specimen donors and relevant research groups associated with this project. This work was supported by funding from the National Health and Medical Research Council of Australia (ID 1008349 to W.D. Tilley; ID 1083961 to L.A. Selth and W.D. Tilley), a Prostate Cancer Research Programs Transformative Impact Award from the US Department of Defense (W81XWH-13-2-0093 to S.R. Plymate, W.D. Tilley, G.V. Raj, S.M. Dehm, and L.A. Selth), and NIH grant R01CA174777 (S.M. Dehm). L.A. Selth was supported by a Young Investigator Award from the Prostate Cancer Foundation (Foundation 14 award). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.