Abstract
Androgen receptor (AR) signaling remains the major oncogenic pathway in prostate cancer (PCa). Androgen-deprivation therapy (ADT) is the principle treatment for locally advanced and metastatic disease. However, a significant number of patients acquire treatment resistance leading to castration resistant prostate cancer (CRPC). Epigenetics, the study of heritable and reversible changes in gene expression without alterations in DNA sequences, is a crucial regulatory step in AR signaling. We and others, recently described the technological advance Chem-seq, a method to identify the interaction between a drug and the genome. This has permitted better understanding of the underlying regulatory mechanisms of AR during carcinogenesis and revealed the importance of epigenetic modifiers. In screening for new epigenomic modifiying drugs, we identified SD-70, and found that this demethylase inhibitor is effective in CRPC cells in combination with current therapies. The aim of this review is to explore the role of epigenetic modifications as biomarkers for detection, prognosis, and risk evaluation of PCa. Furthermore, we also provide an update of the recent findings on the epigenetic key processes (DNA methylation, chromatin modifications and alterations in noncoding RNA profiles) involved in AR expression and their possible role as therapeutic targets.
Highlights
Prostate cancer (PCa) is the most prevalent cancer in men and the third cause of cancer-specific mortality in Western countries [1]
This review focuses on the role of epigenetic processes such as histone methylation, histone acetylation and non-coding RNA that play a central role in the regulation of Androgen receptor (AR) in prostate cancer (PCa) pathogenesis and progression and discusses further modalities of treatment
HDAC1 interacts with the Prostate specific antigen (PSA) promoter and suppresses AR signaling [66] while HDAC7 has the similar ability to inhibit AR, but in this case the mechanism of action is independent of AR acetyl acceptor sites [89]
Summary
Prostate cancer (PCa) is the most prevalent cancer in men and the third cause of cancer-specific mortality in Western countries [1]. The hinge region is a bridge between the DBD and the ligand binding domain (LBD), which accommodates the second activation function (AF2) motif [2]. Cancers 2017, 9, 9 sustained AR activity is inexorable from PCa cell survival and disease progression, even following androgen deprivation therapy (ADT) [3,4]. Since the discovery in the 1940s that PCa is dependent on androgens [5], the central therapy for patients with locally advanced or metastatic disease targets the AR. After an initial period of therapeutic response, PCa become insensitive to these therapies and progresses to the castration resistant prostate cancer (CRPC) [6]. This review focuses on the role of epigenetic processes such as histone methylation, histone acetylation and non-coding RNA that play a central role in the regulation of AR in PCa pathogenesis and progression and discusses further modalities of treatment
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