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Epigenetic readers
The framework of modifications constructed by epigenetic writers requires other cellular proteins to both
recognize and mediate their effects. Epigenetic readers are protein domains that can bind to these
modifications that may be present on DNA and histones. This section will focus on the domains that can be
both and recognize methylation and acetylation and therapeutic approaches in PCa.

Readers of DNA methylation
DNA methylation is a major epigenetic process that regulates chromatin structure which causes
transcriptional activation or repression of genes. The process of DNA methylation is the addition of methyl
groups to the correct bases located on the genome by “writer” molecules, known as DNA
[17]
methyltransferases . DNA methylation can provide two different functions. The first function is that DNA
methylation directly inhibits transcription factor binding at the gene regulatory region, resulting in
transcriptional repression. An alternative operational route is to recruit reader molecules, commonly
referred to as methyl-binding proteins (MBP), at the methylated site, which can then attract various
members of the chromatin remodeling complex, which will result in transcriptional activation or repression
with a dependence on the cellular content. DNA methylation has long been suspected of playing a role in
tumorigenesis and cancer progression in various tissue types. Due to this linkage, several drugs have been
approved by the FDA, such as Vidaza and Dacogen, which act as DNA methylation inhibitors and are
utilized as cancer therapies. These inhibitors operate by reversing the hypermethylated state at the promoter
regions of tumor suppressor genes and induce activation of premetastatic genes. In prostate cancer, it has
been reported that the knockdown of methyl-binding protein 1 (MBP-1), which functions as a general
transcriptional repressor in human PCa cells, results in a delay of cell cycle progression via the inhibition of
[60]
cyclin A and cyclin B1 expression . Additionally, it has been shown that the carboxyl-terminal repressor
domain of MBP-1 (MBP-CR) is sufficient for regression of prostate tumor growth in nude mice and
suggests that MBP-CR expression has an anti-proliferative effect in human prostate cancer cells compared
to the full-length MBP-1 in preventing tumor growth .
[60]
BRD4
The bromodomain-containing family proteins recognize and bind to acetylated lysine residue modifications
of histones or proteins, an important class of acetylation readers. The bromodomain was first reported as an
evolutionarily conserved domain in proteins of humans, flies, and yeast in 1992 . It has approximately 110
[61]
amino acids and consists of four α helices forming a hydrophobic cavity that identifies acetyl-lysine. There
are 42 bromodomain-containing proteins with 61 unique bromodomains In humans, in which differences
of the amino acid residues at the acetyl-lysine binding site determine the specificity of binding . The BET
[62]
(bromodomain and extra terminal domain) subfamily proteins have two conserved amino-terminal
bromodomains (BD1 and BD2) that are pivotal for recognizing acetylated lysine residues of histones and
other non-histone proteins, playing an important role in regulating transcription by recruiting RNA
polymerase II (POL II) . BRD4 is one of the well-studied BET family proteins that recognize either histone
[63]
tail or non-histone acetylated modifications at lysine residues. BRD4 was first described as a MED1-
interacting protein and occupies thousands of enhancers and promoters related to gene activation . BRD4
[64]
also works as a critical regulator of the positive transcriptional elongation factor b (P-TEFb) complex via
recruiting it to the chromatin and mediates the activation of P-TEFb, consequently phosphorylating and
activating RNAPOL II. It is reported that the interaction of BRD4/P-TEFb is crucial for rapid
transcriptional reinitiating after mitosis [65,66] . Besides recognizing histone acetylation, BRD4 also identifies
and binds to the acetylated lysine residues of non-histone. Shi et al. [67,68] discovered that BRD4 identifies
Tip60-diacetylated of Twist and thereby constructing an activated Twist/BRD4/P-TEFb/RNA-Pol II
complex at the WNT5A promoter and enhancer in breast cancer. BRD4 also functions as an atypical kinase
to directly phosphorylate Serine 2 of the CTD of RNA POL II, implicating BRD4 as a regulator of