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| Status |
Public on Apr 01, 2017 |
| Title |
Grainyhead-like 2 is essential for androgen receptor expression and activity in prostate cancer (ChIP-seq) |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
The mainstay treatment for men with metastatic prostate cancer is androgen deprivation therapy (ADT), which inhibits androgen biosynthesis and/or binding of ligand to the androgen receptor (AR). Most men respond to ADT, but all subsequently develop resistance and progression to incurable and lethal castration-resistant prostate cancer (CRPC). CRPC generally remains driven by the AR: therefore, the development of novel AR-targeted therapies, as well as elucidating therapy-driven changes to the AR signalling axis that mediate resistance, remain priorities for the field. Using a novel and powerful proteomic technique, rapid immunoprecipitation of endogenous proteins (RIME), we have identified a new AR binding protein, the transcription factor Grainyhead-like 2 (GRHL2), and shown that it plays an essential, multifaceted role in signalling by the canonical AR and by constitutively active truncated AR variants (ARVs). GRHL2 is necessary for the maintenance of AR/ARV expression in multiple prostate cancer model systems, co-localises with AR at specific sites on chromatin to enhance the androgen-regulated transcriptional program, and is required for optimal prostate cancer growth. Interestingly, we found that GRHL2 is itself an AR/ARV-regulated gene, creating a positive feed-forward loop between the two factors. The GRHL2 gene is frequently amplified and upregulated in CRPC, thereby potentially enabling further amplification AR signalling in the drug-resistant setting. In summary, this study has identified a critical new AR coregulator and potential therapeutic target in prostate cancer.
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| |
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| Overall design |
ChIP-seq for GRHL2 and AR in LNCaP cells
|
| |
|
| Contributor(s) |
Selth L |
| Citation(s) |
28473532 |
| |
| Submission date |
Apr 13, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Luke Selth |
| E-mail(s) |
luke.selth@flinders.edu.au
|
| Organization name |
Flinders University
|
| Department |
College of Medicine and Public Health
|
| Street address |
Flinders Drive
|
| City |
Bedford Park |
| State/province |
SA |
| ZIP/Postal code |
5042 |
| Country |
Australia |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (4)
|
|
| This SubSeries is part of SuperSeries: |
| GSE80452 |
Grainyhead-like 2 is essential for androgen receptor expression and activity in prostate cancer |
|
| Relations |
| BioProject |
PRJNA318399 |
| SRA |
SRP073261 |
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