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Cancer Res. 2017 Jul 1;77(13):3417-3430. doi: 10.1158/0008-5472.CAN-16-1616. Epub 2017 May 4.

Novel Androgen Receptor Coregulator GRHL2 Exerts Both Oncogenic and Antimetastatic Functions in Prostate Cancer.

Author information

1
Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, The University of Adelaide, South Australia, Australia.
2
Freemasons Foundation Centre for Men's Health, Adelaide Medical School, The University of Adelaide, South Australia, Australia.
3
Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, United Kingdom.
4
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
5
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.
6
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
7
Department of Medicine and VAPSHCS, University of Washington, Seattle, Washington.
8
Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, The University of Adelaide, South Australia, Australia. luke.selth@adelaide.edu.au.

Abstract

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. Cancer Res; 77(13); 3417-30. ©2017 AACR.

PMID:
28473532
PMCID:
PMC5497757
DOI:
10.1158/0008-5472.CAN-16-1616
[Indexed for MEDLINE]
Free PMC Article

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