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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Paltoglou, Steve 
Das, Rajdeep 
Townley, Scott L 
Hickey, Theresa E 
Tarulli, Gerard A 

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.

Description

Keywords

Animals, Cell Line, Tumor, Cell Proliferation, Chick Embryo, DNA-Binding Proteins, Humans, Male, Oncogenes, Prostatic Neoplasms, Receptors, Androgen, Transcription Factors, Transfection

Journal Title

Cancer Res

Conference Name

Journal ISSN

0008-5472
1538-7445

Volume Title

77

Publisher

American Association for Cancer Research (AACR)

Rights

All rights reserved
Sponsorship
Cancer Research UK (C14303/A17197)
Cancer Research UK (20411)