Endocrine Abstracts

Prostate cancer (PC) growth is androgen-dependent, hence, the mainstay for treatment is hormone-ablation therapy using anti-androgens, and/or androgen-deprivation therapies. Unfortunately, after a median time of 18 months, the cancer reappears in an androgen independent form, termed castrate-resistant PC (CRPC), which is largely fatal. To date, many molecular mechanisms have been suggested to be responsible for persistent AR signalling in CRPC. AR variants (AR-Vs), short forms of the AR which lack the ligand binding domain (LBD), have been identified as a major mechanism of maintaining AR signalling in castrate conditions. Underpinning mechanisms of AR-V regulation is essential to ablate the transcriptional effects of these transcription factors. Overexpression of pioneer factor such as GATA2, which act to facilitate AR loading on chromatin, have also been reported in CRPC. Taken together, depletion or inhibition of the pioneer factor - AR-V axis could prove useful in ablating AR-V-dependent transcription in castrate conditions. We report that GATA2 knockdown reduces AR-V recruitment to chromatin at specific target gene promoters/ enhancers and regulates ~10% of the AR-V transcriptome. Concordantly, depletion of GATA2 results in reduced proliferation of AR-V driven prostate cancer cell lines. Additionally, the interaction between GATA2 and chromatin was disrupted by a BET inhibitor, JQ1. Data presented here indicates that AR-Vs remain reliant on the pioneer factor GATA2 for maximal transcriptional activity. Removing GATA2 from cis-regulatory elements using BET inhibitors or GATA2-targeted therapies may contrite to creating an inaccessible chromatin environment and attenuate advanced prostate cancer cell growth.

Presenting author: Lewis Chaytor, Northern Institute for Cancer Research, Newcastle University, NE2 4HH, Newcastle upon Tyne, UK. Email: [email protected]-->.