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Page 348 Jones et al. J Transl Genet Genom 2021;5:341-56 https://dx.doi.org/10.20517/jtgg.2021.19

[69]
transcription . Recently, BRD4 also phosphorylates c-MYC at Thr58, resulting in MYC ubiquitination and
[70]
degradation, suggesting BRD4 negatively regulates MYC level . Overall, BRD4 possesses a pivotal role in
the regulation of transcription and protein stabilization.

BRD4 plays an oncogenic role and is a potential target of therapy in various cancers. In CRPC,
Pawar et al. unrevealed that BRD4 physically interacts with AR, and the inhibition of BRD4 disrupts AR
[71]
recruitment to target gene loci and abrogates AR-mediated gene transcription, including induction of the
TMPRSS2-ERG gene fusion and its oncogenic activity. The study provides a novel epigenetic approach for
the concerted blockade of oncogenic drivers in advanced PCa. In addition, in ER+ breast cancer,
Nagarajan et al. discovered that BRD4 occupies distal EREs enriched for the histone H3 lysine 27acetyl
[72]
(H3K27ac) mark and regulates enhancer RNA synthesis by affecting RNAPII recruitment and elongation.
Consistently, BRD4 activity is required for the proliferation of ER+ breast and endometrial cancer cells and
uterine growth in mice. In conclusion, several studies are focusing on BRD4 as a target for therapy. To
inhibit the function of BRD4, a number of selective small-molecules have been developed, which function
by blocking the binding of BRD4 to targeted genes via competing for the acetyl-binding pockets [73,74] . One of
the most popular inhibitors is JQ1, a thieno diazepine-based small molecule, which shows excellent
inhibition against the BET subfamily in the low nanomolar range, and is especially effective against
BRD4 . Currently, at least 10 BET inhibitors (BETis) have participated in clinical trials [Table 1] [75-80] . It is
[74]
well reported that PCa-associated SPOP mutations cause resistance to BETis via BRD4 accumulation . In
[77]
this regard, besides small-molecule inhibitors, a serial of proteolysis targeting chimera (PROTAC) has
[71]
recently been developed to target BET proteins for degradation [78,79] . Pawar et al. found that PROTAC-
BETd (ZBC260) effectively induces BRD4 degradation and results in BETi-resistant cells revers into
sensitive cells to BETis. It suggests that the utilization of both small molecule inhibitors and PROTACs
makes targeted therapy of BRD4 an effective therapy in various cancer models.

Currently, there is a lack of BETis, including JQ1 approved by the FDA for clinic application due to dose-
limiting toxicity. Given that combination treatment is a classic strategy to reduce the monotherapy dosage,
[80]
Mao et al. proposed that the PLK1 inhibitor GSK461364A could synergistically combine with BRD4
inhibitor JQ1 in the treatment of CRPC. The co-inhibition of BRD4 and PLK1 resulted in delayed cell
growth, substantial cell apoptosis, and catastrophic cell cycle arrest in aggressive human CRPC cells. The
significant improvement of efficacy in combining a PLK1 inhibitor and BRD4 inhibitor suggests a novel
therapy for clinical trials.

Epigenetic erasers
Though epigenetic markers in post-translational modifications on histones are covalently linked to DNA,
they are not permanently bound to the structure. Epigenetic erasers are a group of enzymes that maintain
the ability to oppose the activity of writers and catalyze the removal of epigenetic alternations. This removal
relieves its effect on transcription, resulting in the modulation of gene expression . In the section, we
[17]
emphasize the enzyme responsible for removing methyl and acetyl groups while discussing its role in the
prostate and introducing therapeutic tactics.

HDAC
In contrast to histone acetyltransferase transferring acetyl group to histones, histone deacetylases (HDACs)
remove acetyl groups from histones, resulting in a more condensed form of chromatin and gene silencing.
To date, four HDAC classes have been identified in humans [81-83] . Class I HDACs, consisting of HDACs 1, 2,
3, and 8, are mainly localized in the nucleus and expressed in most tissues. Class II, consists of HDACs 4, 5,
6, 7, 9, and 10, are localized both in the nucleus and the cytoplasm. Class III HDACs are homologs of yeast