Molecular Targeting of Prostate Cancer During Androgen Ablation: Inhibition of CHES1/FOXN3
Abstract
Our operating hypothesis is that Checkpoint suppressor 1 (CHES1)/FOXN3 is an androgen withdrawal-induced gene that promotes prostate cancer (PCa) resistance to apoptosis. The purposes of this research are two-fold. The first is to define the mechanisms of CHES1 gene expression regulation and function, particularly in mediating apoptosis resistance during androgen ablation. Secondly, the tools yielded from our functional studies will be utilized to test the efficacy of CHES1- silencing therapy (CST) in preventing castration-resistant prostate cancer (CRPC) and to develop a mechanism-based noninvasive imaging strategy for monitoring the success of CST. Several significant findings were made. We defined the mechanisms through which CHES1 coordinates anti-apoptotic pathways, specifically enhanced PI3K/Akt activation and global regulation of genes negatively regulating apoptosis. We elucidated that CHES1-mediated AR repression diminishes amino acid-activated mTORC1, which consequently de-represses PI3K-Akt activity. We defined the precise mechanism of CHES1 as a direct transcriptional suppressor of pro-apoptotic BNIP3 expression via its ability to recruit co-repressor complexes to the upstream regulatory region. Conversely, p53-mediated CHES1 down-regulation is required for genotoxic stress to trigger apoptosis. Taken together, our findings provide strong support for exploiting CHES1 as a therapeutic target in that CHES1 antagonism would potentially lead to decreased anti-apoptotic PI3K-Akt signaling, combined reinstatement of pro-apoptotic gene expression (i.e., BNIP3) and suppression of pro-survival genes, and reduced activity of oncogenic AR splice variants.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2013
- Accession Number
- ADA599249
Entities
People
- Clifford G Tepper
- Tamlyn Tsubota
Organizations
- University of California