Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

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   Figure 1

   Model for negative feedback loop mediated by AR (AR autoregulation). (A) Recruitment of ligand-bound AR by FoxA1 to an enhancer in intron 2 of the AR gene results in lysine-specific histone demethylase 1 (LSD1)-mediated demethylation of mono- and di-methylated lysine 4 (K4me1 and K4me2, respectively) on histone H3 (LSD1 also demethylates K9 at this loci). Formation of this repressive chromatin environment at the intron 2 enhancer, which also involves the transcription factors GATA2 and Oct1, directly suppresses AR gene transcription via chromatin looping back to the promoter. Chromosome coordinates correspond to hg38 assembly. (B) In a low androgen environment, such as occurs during androgen deprivation therapy (ADT), intron 2 enhancer activity is no longer suppressed by ligand-bound AR and LSD1, resulting in increased AR gene transcription. D, DHT; Me, methyl; Me2, dimethyl; Pol II, RNA polymerase II; TBP, TATA-binding protein. This model is based primarily on data from Cai et al. (2011).
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   Figure 2

   Novel strategies to target persistent androgen receptor signaling in CRPC. Recently approved agents are shown in red; agents in clinical trials are shown in blue; novel agents still in pre-clinical development are shown in green. CoReg, coregulator; HSP, heat shock protein.

• © 2016 Society for Endocrinology