The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis

Abstract

Master transcription factors interact with DNA to establish cell-type identity and to regulate gene expression in mammalian cells1,2. The genome-wide map of these transcription factor binding sites has been termed the cistrome3. Here we show that the androgen receptor (AR) cistrome undergoes extensive reprogramming during prostate epithelial transformation in man. Using human prostate tissue, we observed a core set of AR binding sites that are consistently reprogrammed in tumors. FOXA1 and HOXB13, co-localized with the reprogrammed AR sites in human tumor tissue. Introduction of FOXA1 and HOXB13 into an immortalized prostate cell line reprogrammed the AR cistrome to resemble that of a prostate tumor, functionally linking these specific factors to AR reprogramming. These findings offer mechanistic insights into a key set of events that drive normal prostate epithelium towards transformation and establish the centrality of epigenetic reprogramming in human prostate tumorigenesis.

Pioneer transcription factors shape the epigenetic landscape

“…In ER + breast cancer cells, ER binding requires FOXA1 at many binding sites showing the role of FOXA1 in driving hormone response of these tumors (90). Similarly, AR binding is also influenced by FOXA1; indeed some AR binding sites are lost in cells depleted of FOXA1; however many sites are also gained suggesting a more complex relationship of FOXA1 with AR than with ER (87,91). Also, FOXM1 is amplified in some breast cancers (92), in non-Hodgkin's lymphomas (93) or in malignant peripheral nerve sheath tumors (94).…”

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

“…FOXA1 is a pioneer transcription factor playing an important role in dictating nuclear receptor-binding profiles (Carroll et al 2005;Laganière et al 2005;Zaret and Carroll 2011), including AR in PCa cells (Jin et al 2013;Pomerantz et al 2015), as well as binding to non-AR targets involved in PCa cell cycle progression (Zhang et al 2011). Furthermore, the androgen response element (ARE) was specifically enriched in mTOR-bound regions in the presence of androgens, suggesting targeted corecruitment of mTOR and AR to DNA ( Fig.…”

Current treatment strategies for advanced prostate cancer

“…76 There are some evidence of the interaction between AR signaling and taxanes, including inhibition of AR nuclear localization by taxanes, 69,77,78 AR induced long-non-coding RNA 79 and drug-efflux genes. 80 In addition, it is clear that epigenetic modifications by disease progression affects AR signature leading to tumorgenesis, 81 development of CRPC 82 and drug resistance. 83 Genetic alternations, such as PTEN loss, have been investigated and proved that patients with this loss seem to be associated with worse outcome.…”