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Jones et al. J Transl Genet Genom 2021;5:341-56 https://dx.doi.org/10.20517/jtgg.2021.19 Page 351

MST1 (Hippo homolog) serine-threonine kinase, an AR repressor, and MST1 localization to AR-dependent
promoters is inhibited by depletion of SAFB1. Meanwhile, SAFB1 interacts with Enhancer of Zeste 2
Polycomb Repressive Complex 2 (EZH2) at ARE of chromatin. Knockdown of SAFB1 in androgen-
dependent LNCaP cells results in upregulation of AR and PSA levels, stimulating the growth of cultured
cells and subcutaneous xenografts and promoting a more aggressive phenotype, which is consistent with a
[127]
negative AR regulatory function . Collectively, SAFB1 functions as a tumor suppressor in both breast
cancer and PCa.

Epigenetics and genetic instability
Epigenetics and genetics have been described as separate entities, participating in carcinogenesis via
[128]
independent mechanisms . However, recent publications have unveiled crosstalk that occurs between
[127]
genome and epigenome factors that could produce novel therapeutic strategies in PCa .
Microsatellites are highly polymorphic, short-tandem repeat sequences dispersed throughout the
genome . The instability of these repeats at multiple loci can result in mismatch repair errors and other
[128]
genetic issues. Loss of heterozygosity (LOH) has been reported to strongly correlate with increasing
[129]
malignancy in prostate carcinoma . Recently it has been documented that chromosomal instability,
including MSI/LOH, has been categorized as a distinct type of genetic instability characteristic in regards to
[130]
prostate cancer . Epigenetic processes such as hypermethylation of tumor suppressors, histone
modification, and hypomethylation of oncogenes have been documented to eventually create genetic
instability in the forms of MSI, LOH, allelic loss, single nucleotide polymorphisms (SNPs), and
chromosomal aberrations. DNA methylation alterations could induce loss of heterozygosity and lead to a
progression in prostate cancer . It has been reported ten-eleven translocase 2 (TET2), enzyme-mediated
[129]
DNA demethylation, exhibits high mutation rates (10%-20%) and extensive loss of heterozygosity (~60%) in
metastatic prostate tumors. Genome-wide association studies have also shown increased PCa risk linked to
an intergenic TET2-proximal SNP (rs7679673) . Additionally, Baylin and Jones have reported that cancers
[131]
with hypermethylated MGMT are susceptible to genetic mutations in critical genes such as p53 or KRAS.
MLH1, a mismatch repair gene, plays an important role in genomic instability. It has been reported that
[132]
promoter hypermethylation results in loss of function of this gene and causes MSI in several cancers .

Regarding histone modification, deregulated Polycomb Repressor Complex 2 mediated epigenetic
modifications have been shown to cause genetic instability, malignancy, and cancer development through
abnormal tumor suppressor gene expression, DNA damage response, and DNA replication . BRD4
[133]
acetylates histone H3 at the K122 residue, and this thereby perturbs a salt bridge, leading to nucleosome
instability . It has been recently documented that targeting genetic instability with possible PARP could be
[134]
utilized as a novel therapeutic approach in prostate cancer treatment. Epigenetic changes, such as DNA
hyper- and hypomethylation, can cause genetic instability, such as LOH/MSI, in various cancer types.
Multiple genetic and epigenetic abnormalities in PCa suggest that co-targeting both epigenetic changes and
genetic instability could become a novel therapeutic strategy in PCa treatment.

CONCLUSION
AR has been a critical target for the treatment of PCa, and while ADT has been effective in preventing
cancer cell proliferation, progression to a more aggressive phenotype is inevitable. In this review, we
discussed the various epigenetic changes which contribute to the further advancement and progression of
PCa via the activation of various oncogenic pathways. We also explored novel therapeutic approaches
established by our lab and drug treatment strategies that have demonstrated impactful success. Due to
recent discoveries in the understanding of the mechanisms of maintained AR signaling in castration-