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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 349

silent information regulator 2 and consist of SIRT 1-7. Class IV HDAC consists of HDAC 11. Class I, II, and
IV HDACs have a zinc coordinated active site, whereas Class III HDACs are dependent on coenzyme
nicotinamide adenine dinucleotide for deacetylase activity.

HDAC role in PCa and therapeutic approaches
In cancer cells, high expression of HDACs results in the deacetylation of histone proteins, which causes
DNA to be wrapped tightly by histones, thereby inhibiting gene expression. If the affected genes are tumor
suppressors, the neoplastic proliferation of cells and cancer may result . It has been reported that Class I
[83]
HDACs (HDAC 1, 2, and 3) are highly expressed in PCa, specifically in CRPC [84,85] . Additionally, evidence
has shown HDACs play a positive role in regulating the AR protein level and its transcriptional activity [86-88] .
Therefore, it seems that HDACs could exhibit opposing pro- and anti-tumorigenic roles in PCa cells. In
addition, HDAC inhibition could induce cell cycle arrest, apoptosis, autophagy, and reactive oxygen species
generation [82,89] . The support from these discoveries has led to the initiation of several clinical trials of
HDACs inhibitors in PCa treatment, including vorinostat, pracinostat, panobinostat, and romidepsin.
However, none were recommended to continue phase III trials due to either toxicity or disease
[82]
progression . In summary, the function of HDAC in PCa and whether HDAC could be an effective target
in the treatment of PCa is still ambiguous and requires further investigation to reach a conclusion.

Demethylase of histones
Histone lysine demethylases (KDMs) are a class of enzymes that can remove methyl groups from nucleic
[90]
acids, proteins, and specifically histones. The first human KDM was reported in 2004 .To date, several
lysine-specific demethylase isoforms were discovered and characterized. Since their discovery, KDMs have
been found to be deregulated in various cancers, such as non-small cell lung, breast, colorectal, pancreatic,
etc. [87,91] . In PCa, KDMs may act as either tumor suppressors or oncogenes, which is dependent on the genes
regulated by the KDMs.

[92]
Recently, Gao et al. found that KDM1A is demethylation of FOXA1 at K270, and methylation of this
residue decreases FOXA1 stability and activity. Inhibition of KDM1A, therefore, induces FOXA1 instability
and results in FOXA1 chromatin dissociation, thus leading to loss of AR transcriptional activity. Consistent
with this finding are several previously completed studies [93-95] , which have demonstrated that KDM1A is
required for the AR transcriptional activity regulation, both AR and AR variants, confirming its
[96]
involvement in the progression of PCa. Interestingly, a recent study showed that KDM1A could promote
the survival of PCa cells independently of its demethylase function. This effect is explained by the activation
of a lethal PCa gene network in collaboration with KDM1A’s binding protein, ZNF217. Numerous KDM1A
inhibitors, such as TCP, ORY-1001, GSK-2879552, IMG-7289, INCB059872, CC-90011, and ORY-2001,
[97]
have been reported and are presently being investigated in clinical trials for cancer treatment [Table 1] .
Several have exhibited significantly improved potency and selectivity. In addition to KDM1A, KDM3A ,
[94]
KDM4A/4B [98-101] , and KDM6A/6B were also identified as coactivators of AR and play critical roles in PCa
[102]
progression, thus characterizing them as potential therapeutic targets. These findings highlight the roles of
KDMs in PCa initiation and progression, suggesting that targeting KDMs’ activity may provide a new
strategy for PCa treatment.

Chromatin remodelers
Due to the budding advancements in high-throughput epigenomic approaches, visualizing chromatin
structures and how their alternations result in disease development and progression has become an
increased area of study . Chromatin remodeling can be defined as the rearrangement of chromatin from a
[103]
condensed state to a transcriptionally accessible state . This rearrangement allows for transcription factors
[104]