Prostate cancer (PCa) is one of the leading and most obvious malignancies in men nowadays, globally. Advanced stages of PCa are associated with considerable mortality in men and have remained a significant clinical concern. Most PCa cases are initially androgen-sensitive and depend on the androgen-androgen receptor (AR) signaling axis for the disease’s initiation, promotion, and progression. However, the advanced stage of PCa usually grows independent of androgen signaling and is designated as castration-resistant PCa (CRPC). Such cancers grow aggressively with a poor prognosis. Androgens (male sex hormones), such as testosterone and dihydrotestosterone (DHT), are essential for the development of the reproductive system and secondary sexual traits in males (Mooradian et al., 1987, Wilson, 1999). However, abnormal androgen activity also underlies various pathological conditions, including PCa (Emmelot-Vonk et al., 2008, McCarthy, 2011, Spada et al., 1991, Zitzmann, 2009). Androgen signaling involves AR-mediated transactivation of downstream genes through canonical genomic pathways. DHT binds to AR, induces conformational changes, and sets it free from its cytosolic tethering proteins such as HSP90 and other chaperones. The binding of DHT to AR stabilizes it by allowing its interaction with other cytosolic proteins, such as importin-α, filamin A, etc. This interaction facilitates the nuclear localization of AR, where its dimeric form binds to a DNA sequence that constitutes the androgen response elements (AREs) found in the promoter regions before the start of the transcription site of different target genes present before the transcription initiation site (Heinlein & Chang, 2004). AR-mediated transactivation of multiple genes is involved in the regulation of several important processes, including cell cycle regulation, growth and proliferation, stemness, etc. However, the activity of some co-regulatory proteins plays a critical role in the regulation of transcriptional activity of ARE-bound AR. Coregulatory proteins are known to interact with AR to enhance transactivation (coactivators) or reduce transactivation (corepressors). Some examples of coactivator proteins are CAF, Tip60, p300, GRIP1/ TIF2, SRC-1, and CBP, etc. (Heinlein & Chang, 2002), and few of them possess intrinsic histone acetyltransferase (HAT) activity.

Non-canonical pathways also mediate the action of androgen during PCa development, which is independent of canonical AR signaling (Sen, Prizant, & Hammes, 2011). Such actions are usually regulated by G-protein coupled receptor proteins or membrane-bound androgen receptors (e.g., ZIP9) (Thomas, Converse, & Berg, 2018). In addition, various epigenetic modifications such as DNA methylation, Histone deacetylation, Histone demethylation, etc., also play a role in the regulation of androgen-AR signaling and are subsequently involved in the pathology of PCa by facilitating AR-dependent gene expression(Gao & Alumkal, 2010; Heinlein & Chang, 2002). Epigenetics refers to some heritable but reversible modifications in a gene without altering the DNA sequence. Epigenetic modifications mainly involve the addition of methylation marks in DNA at CpG sites of the promoter regions (DNA methylation), histone modifications (acetylation, methylation, etc.), and non-coding RNAs [e.g., micro RNAs (miRNA) and long non-coding RNAs (lncRNAs)]-mediated transcriptional control of target genes. Histone demethylases domain-containing 2 C (JMJD2C), etc., are frequently expressed or overexpressed in PCa (e.g., as Lysine-specific demethylase 1 (LSD1), Jumonji domain-containing 2 C (JMJD2C), etc.). Activation of AR by these coregulators is mostly androgen-dependent, but in some cases, it acts independently of androgen action as well (Gao & Alumkal, 2010; Metzger et al., 2005; Wissmann et al., 2007). Epigenetic modifications are widely associated with different phenotypes of PCa, such as androgen-sensitive, metastatic castration-resistant PCa (CRPC) and neuroendocrine PCa (NEPC). Given the reversibility of epigenetic changes, therapies targeting several epigenetic modifications are intense investigations to develop novel and effective paradigms to manage the PCa in the clinic. In this chapter, we have emphasized key epigenetic modifications underlying abnormal AR signaling, the role of androgens as epigenetic modulators, and epigenetics-based therapeutic strategies to treat PCa effectively. Moreover, the challenges associated with epigenetics-based therapies and strategies to design novel therapeutic interventions are discussed.