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[11]
DNA, RNA, non-coding RNAs, protein, and other chromatin remodeling events . Regarding the study of
PCa, these aberrant alternations have reinforced the establishment of a context-specific translational profile
that favors self-renewal, survival, and invasion and has demonstrated that the accumulation of epigenetic
aberrations eventually causes genetic or genomic instability [Figure 1]. Additionally, AR is demonstrated to
function in conjunction with various chromatin remodelers and epigenetic players that regulate prostate
development and its progression to a malignant phenotype. This review will discuss the essential epigenetic
alternations that are critical in comprehending PCa etiology and developments that highlight new
biomarkers and therapeutic approaches to PCa.

EPIGENETIC REGULATORS OF PCA
Epigenetic writers
Epigenetic codes have commonly been documented to be regulated by writers, readers, and erasers. Writers
[11]
hold the responsibility to transcribe the epigenetic modifications of DNA and histone proteins . These
modifications transpire from the addition of various chemical groups utilizing numerous enzymes. An
invariable number of modifications have the potential to materialize, but for this review, we will focus on
the reactions of methylation and acetylation. DNA and histone proteins are highly prone to methylation,
which is the addition of a methyl group to a DNA molecule that may result in a change in the activity of the
DNA segment, but will not modify the sequence. Routinely, acetylation is a process in which an acetyl
functional group is transferred from molecule to an adjacent molecule and functions by removing the
positive charge, thus reducing the N-termini interaction that contains negatively charged phosphates of
DNA, exclusively in histones. In this area, we will focus on the addition of these modifications and how they
affect the progression and severity of PCa. We will also explore therapeutic methodologies that have been
established to address these alterations in function.

DNMT and DNA methylation
DNA methylation often plays a role in suppressing gene transcription when located in a gene promoter.
DNA methyltransferases (DNMTs) are responsible for transferring methyl groups from the methyl donor S-
adenosyl-L-methionine to the 5-position of cytosine residues in DNA, which is critical for mammalian
development. The DNMT family has five members, including DNMT1, DNMT2, DNMT3a, DNMT3b, and
DNMT3l . DNMTs play an important role in genome integrity as their disruption may lead to
[12]
chromosomal instability and tumor progression [12,13] . The main function of DNMT1 is to maintain the
[14]
methylation status of DNA. As an RNA methyltransferase, DNMT2 usually methylates multiple tRNAs .
DNMT3a and DNMT3b are reported to contribute the de novo DNA methylation.

DNMT3l improves the catalytic activities of DNMT3a and DNMT3b, resulting in the promotion of DNA de
novo methylation by interacting with DNMT3a and DNMT3b . DNA methylation has been shown to play
[15]
a role in PCa, and DNA methylation marks have been studied for their diagnostic and prognostic values.
One of the most recognized DNA methylation events in prostate carcinogenesis is the hypermethylation of
the regulatory region of GSTP1, leading to a decrease in gene expression. This hypermethylation event has
been found in more than 90% of prostate adenocarcinoma samples and studied for its potential diagnostic
and prognostic value . Other studies have shown that various genes such as APC, RASSF1a, PTGS2,
[16]
MDR1, GSTM2, and PENK are hypermethylated in primary and metastatic PCa cells compared to normal
prostatic tissues, suggesting that DNA methylation becomes deregulated and may play a role in the prostate
carcinogenesis process . Both DNA hypermethylation and DNA hypomethylation correlate with prostate
[16]
carcinogenesis and progression. In a study of 10 normal prostates and 45 prostate tumors, 61 genes were
found to be hypermethylated in more than 20% of tumors. A cluster of tumors with hypermethylation of
ETV1 and ZNF215 was correlated with ADT resistance in these patients, suggesting a potential use for