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Page 342 Jones et al. J Transl Genet Genom 2021;5:341-56 https://dx.doi.org/10.20517/jtgg.2021.19

[1]
cancer-related death in United States of America males . Numerous studies have documented that
androgen receptor (AR) signaling continues to participate as a vital component to the development and
progression of PCa. AR is a nuclear hormone receptor that becomes activated upon the binding of androgen
ligands and dissociates from cytoplasmic chaperone protein HSP90, where it then can self-dimerize and
translocate to the nucleus . AR has the ability to bind to androgen response elements (ARE), which results
[2]
in the transcription of target genes and contribution to prostate development and maintenance . In early
[2]
diagnosed stages of the disease, there are successful treatment options to prolong patient survival, such as
medical or surgical castration that distribute AR binding, including radical prostatectomy, radiotherapy, or
androgen deprivation therapy (ADT). However, PCa can reoccur after these interventions, which is
referenced as castration-resistant PCa (CRPC).

CRPC is defined as cancer that continues to proliferate in the absence or depletion of testosterone,
compared to early stages that require higher levels of testosterone for survival and formation, but AR
signaling remains an essential contributor to PCa progression. This led to the synthesis of Androgen-
Signaling Inhibitors (ASI), such as Abiraterone and Enzalutamide (ENZ), which targets androgen synthesis
and AR, respectively. Though ASI treatment options have shown impressive results in reducing PCa,
enviably, within several months, the disease will progress into terminal ASI-resistant PCa. Currently, there
are several various areas of study arising to address the issue of overcoming ASI resistance. Abiraterone
acetate is a hormonal treatment for metastatic CRPC (mCRPC) both before and after chemotherapy and
significantly reduces androgen production by blocking the enzyme, which illustrates its efficacy . ENZ is a
[2]
second-generation nonsteroidal antiandrogen utilized in the treatment of mCRPC patients and has shown
efficacy to provide patients with a reasonable quality of life . Though there has been significant success
[3]
associated with the administration of these treatments, resistance does occur with both Abiraterone and
ENZ, possibly from the development of splice variants . Wnt signaling has been extensively documented in
[3]
its involvement in ENZ resistance. The inhibition of both canonical and non-canonical Wnt signaling has
demonstrated positive results in re-establishing sensitivity to ENZ treatment in resistant cell lines and
tumor models .
[3-5]
Additionally, we have established that 3-hydroxy-3-methyl-glutaryl-CoA reductase, a crucial enzyme in the
mevalonate pathway, is elevated in ENZ-resistant PCa cells, and combination therapy of simvastatin and
ENZ could result in significant inhibition of ENZ-resistant cancer cell proliferation in both in vivo and in
vitro models . Even in terms of AR splice variants, which play a critical role in the development and
[6]
[7]
[8]
progression of CRPC . Wang et al. demonstrated that treatment with Malat1 small interfering RNA
inhibits ARV7 expression in cell lines and significantly reduces tumor growth in ENZ-resistant xenografts.
[9]
Additionally, Yamamoto et al. demonstrated that using antisense oligonucleotides to target both the full-
length AR and its splice variants resulted in a suppression of ENZ-resistant cell lines and xenografts
proliferation. Due to the increase in understanding the molecular mechanisms that drive PCa, there has
been a rising interest in epigenetics related to new therapeutic approaches.

Epigenetics is the study of heritable changes in gene expression, subsequently controlling fate, without
[10]
affecting actual DNA sequences . An abundance of exploration has been accomplished in epigenetics since
it was first introduced and defined in the 1950s by Conrad Waddington. These recent discoveries have led
to the emergence of operational mechanisms that are composed of three processing steps. These steps can
be defined as epigenator, which is a signal that originates from the cellular environment and initiates
downstream signaling pathways . The epigenetic initiator, which triggers the epigenetic modification at a
[11]
specific chromatin structure and the epigenetic maintainers that are epigenetic code responsible for
ensuring several events such as chemical modifications on DNA or histones molecules, interacts between