Abstract
Prostate cancer (PCa) is a top-incidence malignancy, and the second most common cause of death amongst American men and the fifth leading cause of cancer death in men around the world. Androgen receptor (AR), the key transcription factor, is critical for the progression of PCa by regulating a series of target genes by androgen stimulation. A number of co-regulators of AR, including co-activators or co-repressors, have been implicated in AR-mediated gene transcription and PCa progression. Epigenetic regulators, by modifying chromatin integrity and accessibility for transcription regulation without altering DNA sequences, influence the transcriptional activity of AR and further regulate the gene expression of AR target genes in determining cell fate, PCa progression and therapeutic response. In this review, we summarized the structural interaction of AR and epigenetic regulators including histone or DNA methylation, histone acetylation or non-coding RNA, and functional synergy in PCa progression. Importantly, epigenetic regulators have been validated as diagnostic markers and therapeutic targets. A series of epigenetic target drugs have been developed, and have demonstrated the potential to treat PCa alone or in combination with antiandrogens.
Highlights
Prostate cancer (PCa) is the second most commonly diagnosed cancer type and the fifth leading cause of cancer death in men around the world (Bray et al, 2018)
We summarized the known epigenetic regulators, including readers, writers, and erasers working together with Androgen receptor (AR) in PCa progression, and discussed their potential as epigenetic diagnostic and therapeutic targets, as well as future translational applications for PCa
Long Non-Coding RNAs LncRNAs primarily interact with mRNA, DNA, protein, and micro RNAs (miRNAs) and regulate gene expression through epigenetic mechanisms
Summary
Prostate cancer (PCa) is the second most commonly diagnosed cancer type and the fifth leading cause of cancer death in men around the world (Bray et al, 2018). AR co-regulators, recruited by the individual domains of AR protein, modify the epigenetic conditions around the ARE binding motifs in the chromatin, thereby affecting the transcriptional activity of AR. The hinge region of AR regulates the epigenetic pathway, especially the acetylation of its 629-RKLKKL-634 motif, which plays key roles in DNA binding, co-activator recruitment and the N/C interaction, and is a target site of acetylation, methylation and ubiquitination (Clinckemalie, et al, 2012; Fu et al, 2006).
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