Targeting epigenetic effects of androgen-androgen receptor signaling in prostate cancer

Prostate cancer (PCa) is a multifaceted and heterogeneous disease that affects men globally. PCa incidences and related deaths in men are a major clinical challenge that needs immediate attention to prevent, manage, or treat the disease to improve overall health in patients. Activation of androgen receptor (AR) signaling and subsequent transactivation of downstream genes play a predominant role in PCa development, progression, and metastasis. Over the last few decades, the role of epigenetics has been much appreciated in the pathogenesis of PCa. There is widespread involvement of several epigenetic changes (such as DNA modifications by methylation, histone modifications by acetylation, chromatin remodellers, and non-coding RNAs, etc.) in the regulation of PCa initiation, progression, as well as the emergence of androgen-insensitive castration-resistant PCa (CRPC) phenotype, which has improved our understanding of disease etiology. Moreover, targeting selective epigenetic marks has raised immense opportunities to target PCa, owing to the possibilities of reversal of epigenetic changes involved in the disease progression. Several epigenetic inhibitors (e.g., DNMT inhibitors, HDAC inhibitors) have been investigated in preclinical studies as well as in clinical trials to establish effective epigenetic-based therapies against PCa, and indeed, few of them have already made their way to the clinic. Epigenetics also plays a role in the reactivation of AR signaling in CRPC; though hormonal therapies are ineffective in these tumors, epigenetic inhibitors combined with other therapies are considered important in targeting CRPC. Here, we have summarized epigenetics in the regulation of AR signaling, progress in understanding epigenetics' role in etiology, and the importance of designing effective therapies for PCa, including CRPC. We have also discussed the limitations and challenges in epigenetics therapies and strategies to overcome obstacles in improving existing therapies to better manage PCa disease in clinics.