Factors that influence the androgen receptor cistrome in benign and malignant prostate cells

Abstract

The androgen receptor (AR) plays key roles in the development of prostate tissue and the development and progression of prostate cancer (PC). AR guides cytodifferentiation and homeostasis in benign luminal epithelial cells; however, in PC, AR instead drives the uncontrolled proliferation of these cells. This ‘AR malignancy shift’ (AMS) is a central event in tumorigenesis. Using a ChIP‐seq approach in primary human tissues, cell lines, and mouse models, we demonstrate that the AMS occurs in every sample analyzed, suggesting that it is necessary for PC development. Using molecular and genetic techniques, we demonstrate that forkhead box (FOX)A1, HOXB13, GATA2, and c‐JUN are involved in the regulation of the AMS. AR‐binding sites (ARBS) are enriched for FOX, HOX, and GATA motifs in PC cells but not for c‐JUN motifs in benign cells. We show that the SPOP mutation commonly found in localized PCs can cause the AMS but is not transformative on its own and must be coupled to another mutation to transform cells. We show that the AMS occurs in mouse models of PC as well and that chronic low T, which is associated with increased PC risk and aggressiveness in humans, also causes the AMS in mice. We have discovered a previously unrecognized, fundamental tenet of PC, one which explains how and why AR signaling is different in cancer and benign cells. Our work has the potential to be used to stratify patients with localized PC for specific treatments. Furthermore, our work suggests that the AMS is a novel target for the treatment and/or prevention of PC.

Darolutamide antagonizes androgen signaling by blocking enhancer and super‐enhancer activation

“…sequences and cooperating DNA-binding factors to support AR binding (Toropainen et al, 2016;Wilson et al, 2016). In line with this, a set of reprogrammed AR-binding regions characterized by FOXA1 and HOXB13 colocalization is acquired in prostate tumors (Copeland et al, 2019;Pomerantz et al, 2015). FOXA1 acts upstream of the AR (Zhao et al, 2016), and we show here that darolutamide decreased androgen-stimulated FOXA1 occupancy, probably as a consequence of the blockade of AR binding.…”

“…AR signaling has an essential role in the normal male physiology but also fuels growth, proliferation, and metastasis of PCa (Wang et al, 2007;Wang et al, 2009;Xu et al, 2006). This malignant role is due to an aberrant AR cistrome found in tumor cells which activates downstream cancerous pathways (Armenia et al, 2018;Copeland et al, 2019;Pomerantz et al, 2015;Wang and Koul, 2017;Wang et al, 2009). AR-controlled enhancers are marked by histone acetylation, H3K4 monomethylation, and binding sites for AR itself as well as dedicated coregulators such as FOXA1 (Taslim et al, 2012).…”

Reshaping of the androgen-driven chromatin landscape in normal prostate cells by early cancer drivers and effect on therapeutic sensitivity

“…SPOP mutation was sufficient to reprogram the AR cistrome to one with a resemblance to human PCa. Interestingly, one other study reported different effects on the AR cistrome in response to SPOP mutation introduced into established cell lines with multiple alterations ( Copeland et al, 2019 ), with expansion of the AR cistrome toward both normal and tumorigenic sites. The more profound shift we report here may reflect the value of genetically normal models in studying initiation events, and suggest that oncogenic reprogramming of the AR transcriptional program may be a very early event in the natural history of PCa, at least in selected subtypes.…”

“…FOXA1 is a key pioneering factor for AR and HOXB13 TFs, facilitating binding to PCa-specific AR bound sites. Furthermore, FOXA1 and HOXB13 overexpression transforms AR cistrome from normal, immortalized cell lines into an oncogenic one ( Copeland et al, 2019 ; Pomerantz et al, 2015 ). Our study suggests a significant role for FOXA1 in SPOP mutant prostate organoids, consistent with observations in human tumors.…”

Hydroxychloroquine Blocks Autophagy and Promotes Apoptosis of the Prostate after Castration in Rats

“…Treatment for advanced prostate cancer is de-androgen therapy recently, but after about 18-24 months, most of the patients become drug resistant [1][2][3]. Therefore, finding out the mechanism of prostate cancer drug resistance and blocking the occurrence of drug resistance have become an urgent problem to be solved clinically.…”