Persistent androgen receptor-mediated transcription in castration-resistant prostate cancer under androgen-deprived conditions

Abstract

The androgen receptor (AR) is a ligand-inducible transcription factor that mediates androgen action in target tissues. Upon ligand binding, the AR binds to thousands of genomic loci and activates a cell-type specific gene program. Prostate cancer growth and progression depend on androgen-induced AR signaling. Treatment of advanced prostate cancer through medical or surgical castration leads to initial response and durable remission, but resistance inevitably develops. In castration-resistant prostate cancer (CRPC), AR activity remains critical for tumor growth despite androgen deprivation. Although previous studies have focused on ligand-dependent AR signaling, in this study we explore AR function under the androgen-deprived conditions characteristic of CRPC. Our data demonstrate that AR persistently occupies a distinct set of genomic loci after androgen deprivation in CRPC. These androgen-independent AR occupied regions have constitutively open chromatin structures that lack the canonical androgen response element and are independent of FoxA1, a transcription factor involved in ligand-dependent AR targeting. Many AR binding events occur at proximal promoters, which can act as enhancers to augment transcriptional activities of other promoters through DNA looping. We further show that androgen-independent AR binding directs a gene expression program in CRPC, which is necessary for the growth of CRPC after androgen withdrawal.

Androgen receptor co-regulatory networks in castration-resistant prostate cancer

“…The differential activation of biological pathways further supports a divergent transcriptional program regulated by AR in CRPC, which likely serves to meet the changing needs of cancer cells as the disease progresses. Consistent with the patient tumor findings, others have also reported distinct AR binding events in CRPC cell line models, C4-2B and LNCaP-abl (Decker et al 2012). Specifically, AR binding events in CRPC activated mitotic cell cycle genes that help to drive cell proliferation (Decker et al 2012).…”

“…While it is accepted that continued activation of AR signaling axis facilitates the development of CRPC, a critical question that remains is whether diverse AR-mediated transcriptional program and gene networks are in play in androgen-dependent and CRPC. While the early study by Holzbeierlein et al (2004) reported similarities in overall gene profiles of androgendependent and CRPC, recent studies are beginning to identify important differences in the expression of specific genes following transition of prostate cancer from an androgen-dependent state to one that is androgenindependent, reflecting distinct AR transcriptional regulatory programs in the two stages of prostate cancer , Decker et al 2012, Sharma et al 2012.…”

Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts

“…The majority of these studies have been conducted on prostate cancer cell lines and considerable effort has been made in defining AR targets in tumour epithelium [12][13][14][15][16][17]. This has revealed a transcriptional role for AR in tumour cells regulating cell proliferation, metabolism, survival and DNA repair [18,19].…”

“…This has revealed a transcriptional role for AR in tumour cells regulating cell proliferation, metabolism, survival and DNA repair [18,19]. Prostate cancer cell lines have also been used to determine the changes in AR transcriptional networks in both a hormonenaïve-and castrate-resistant setting and numerous studies have revealed distinct binding profiles in the androgen-independent setting [13,17,18,20,21]. More recently, the genomic binding profile of AR variants have also been explored and have been shown to compensate for full length AR in an endocrine therapy-like setting [22].…”

MicroRNA-511 Binds to FKBP5 mRNA, Which Encodes a Chaperone Protein, and Regulates Neuronal Differentiation

“…ChIP analyses were conducted as described previously (42). In brief, HEK293T cells were transfected with human GR cDNA in charcoal-stripped medium for 40 h and treated with vehicle or 10 nM dexamethasone for 4 h. The cells …”