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Page 346 Jones et al. J Transl Genet Genom 2021;5:341-56 https://dx.doi.org/10.20517/jtgg.2021.19

Table 1. Inhibitors for epigenetic changes
Inhibitor Target Clinical trial phase
CM-272 G9a Not in clinical trial
UNC-0638 G9a Not in clinical trial
TCP KDM1A Phase 1/2
ORY-1001 KDM1A Phase 1
GSK-2879552 KDM1A Phase 1/2
IMG-7289 KDM1A Phase 2
INCB059872 KDM1A Phase 1/2
CC-90011 KDM1A Phase 1
ORY-2001 KDM1A Phase 2
BET (JQ1) BRD4 Phase 1

CM-272: 6-methoxy-2-(5-methylfuran-2-yl)-N-(1-methylpiperidin-4-yl)-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-amine; UNC-06358: 2-
cyclohexyl-6-methoxy-N-(1-propan-2-ylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-amine; BET: bromodomain and extra terminal
domain; JQ1: (S)-tert-butyl 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate; TCP:
tranylcypromine; ORY-1001: idademstat; IMG-7289: bomedemstat HCL; INCB059872: 1-((4-(methoxymethyl)-4-((((1R,2S)-2-
phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)cyclobutane-1-carboxylic acid compound with 4-methylbenzenesulfonic acid (1:2); CC-
90011: besylate; ORY-2001: vafidemstat.

EZH2 can bind to the promoter of PSA, resulting in the suppression of its transcription, concluding that
pharmaceutical inhibition of EZH2 can overcome ENZ-resistance in CRPC . Our findings suggest that the
[51]
inhibition of EZH2 via existing FDA-approved EZH2 inhibitors can increase the efficacy of ENZ treatment,
providing terminal CRPC patients with a novel therapeutic strategy. In addition, we also illustrated EZH2
inhibition could enhance the anti-neoplastic activity of metformin in PCa by reducing the binding of AR to
the miR-26a-5p promoter . Collectively, these findings suggest that EZH2 could be an effective therapeutic
[52]
target for PCa, particularly for AR-positive CRPC.

p300/CBP and histone acetylation
Histone acetyltransferase p300 and its highly homologous CREB-binding protein (CBP) attach acetyl
groups to proteins, including histones, in which DNA is wrapped [53,54] . Histone acetylation is a critical
method that governs chromatin. When histones are acetylated, chromatin structures in that region will gain
a loose conformation, and gene transcription will be promoted . It has been reported that p300 and CBP
[54]
were implicated in the progression of PCa and that deletion of p300 in mice limited PCa progression and
extended mice survival . The oncogenic roles of p300/CBP in the progression of PCa are usually related to
[55]
the regulation of AR, the key driver of PCa. p300 can directly acetylate AR, or bind with AR, to enhance its
transcriptional activity, consequently inducing oncogenes expression and promoting tumor growth [55-57] . In
addition to enhancing AR transcriptional activity, p300 can also regulate AR protein level by preventing its
[55]
degradation . These findings highlight p300 as a compelling target for PCa treatment. Indeed, studies have
shown that targeting p300/CBP inhibited both androgen-sensitive and CRPC cell growth [53,57,58] . In addition,
our lab has recently reported a novel mechanism underlying p300 involvement in PCa progression by
upregulating PD-L1 expression, thus creating an immune cell-free microenvironment for tumor
progression. We found that p300 was recruited to the promoter of CD274 (encoding PD-L1) by
transcription factor IRF-1 and resulted in acetylation of histone H3 at the CD274 promoter, and
subsequently CD274 transcription. The p300/CBP inhibitor blocked the transcription of CD274 and
hindered exosomal PD-L1 secretion. Cutting off PD-L1 secretion at transcription by inhibiting p300/CBP in
combination with anti-PD-L1 antibodies demonstrated increased efficacy in a syngeneic mouse model of
PCa . Our discovery suggests that p300 is not only a modifier but also a co-driver for PCa progression,
[59]
confirming that p300 could be a compelling target for PCa treatment.