Abstract
This review will provide a description of recent efforts in our laboratory contributing to a general goal of identifying critical determinants of prostate cancer growth in both androgen-dependent and -independent contexts. Important outcomes to date have indicated that the sustained activation of AR transcriptional activity in castration-resistant prostate cancer (CRPC) cells results in a gene expression profile separate from the androgen-responsive profile of androgen-dependent prostate cancer (ADPC) cells. Contributing to this reprogramming is enhanced FoxA1 recruitment of AR to G2/M phase target gene loci and the enhanced chromatin looping of CRPC-specific gene regulatory elements facilitated by PI3K/Akt-phosphorylated MED1. We have also observed a role for FoxA1 beyond AR signaling in driving G1/S phase cell cycle progression that relies on interactions with novel collaborators MYBL2 and CREB1. Finally, we describe an in-depth mechanism of GATA2-mediated androgen-responsive gene expression in both ADPC and CRPC cells. Altogether these efforts provide evidence to support the development of novel prostate cancer therapeutics that address downstream targets of AR activity as well as AR-independent drivers of disease-relevant transcription programs.
Highlights
The androgen receptor (AR), a member of the steroid receptor superfamily [1], is a classic example of a ligand-inducible transcription factor whose activity is tightly linked to numerous physiological processes and disease states
We have explored the therapeutic approach of targeting downstream products of AR transcriptional activation that contribute to the growth of castration-resistant prostate cancer (CRPC) by investigating the use of cell-cycle inhibitor 779 (CCI-779), targeting mTOR activity [56]
We showed that enhanced locus looping between the AR/GATA2/FoxA1-bound ABCC4 enhancer and promoter follows androgen stimulation and that silencing of either GATA2 or FoxA1 resulted in lost MED1 recruitment and inhibited basal chromatin loop formation
Summary
The androgen receptor (AR), a member of the steroid receptor superfamily [1], is a classic example of a ligand-inducible transcription factor whose activity is tightly linked to numerous physiological processes and disease states. Emerging from the earliest efforts of our lab, this review will highlight the central importance of the pioneer transcription factors GATA2 and FoxA1 in models of early and late stage disease by describing the manner in which FoxA1 directs CRPC-specific AR binding and drives androgen-independent cell cycle progression and the in-depth mechanism by which GATA2 contributes to androgen/AR-mediated gene expression in both ADPC and CRPC. In addition to highlighting how the coordinated activities of these factors with the Mediator coregulatory complex subunit MED1 has been shown to facilitate chromatin loop formation/maintenance allowing for enhancer-driven expression of AR target genes, this review will discuss our work in revealing the relative importance of MED1 in various cell line models of prostate cancer
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