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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 345

G9a and histone Methylation
G9a, a histone methyltransferase, has the capacity to di-methylate histone 3 at lysine position 9. This
[23]
epigenetic modification generally represses gene expression . However, several studies have demonstrated
that G9a also functions as a coactivator of nuclear receptors, such as AR [24,25] . Despite the epigenetic function
of G9a, the first example of G9A operating as a non-histone lysine methyltransferase, reported that G9A
[26]
could auto-methylate at the end of its N-terminal . Following this trend, CDYL1, WIZ, and ACINUS were
discovered as G9A substrates via peptide arrays , suggesting that G9A mediated lysine methylation is
[27]
critical for both histone and non-histone proteins. It has been observed that G9a is overexpressed in a
number of cancers [28,29] , and elevated G9A protein and its enzymatic activities have been determined under
hypoxia stress. For example, Reptin and Pontin, two chromatin remodeling factors, can be methylated by
G9A through hypoxia-dependent manners [30,31] . Furthermore, methylated Retin contributes to tumor growth
and invasive activities via negative regulation of HIF1. Additionally, hypoxia-induced Pontin methylation
enhances the ability of proliferation and invasion in breast cancer cells. An alternative study showed that
hypoxia-mediated G9A also suppressed RUNX, a tumor suppressor, through histone modification. In
addition, hypoxia-mediated G9A amplification decreases apoptosis and increases immature stem-like
cancer cells . In contrast, hypoxia-mediated G9A represses cell adhesion molecules and contributes to
[32]
[33]
breast tumor motility . Additionally, G9A can also promote breast cancer cell survival through driving
hypoxia-mediated gene expression. These impacts on cell malignant behavior potentially are caused by FIH-
mediated G9A/GLP hydroxylation . In addition, G9a also has been found to contribute to the aberrant
[34]
metabolism of cancer cells. Increased G9a can epigenetically activate the serine biosynthesis, which in turn
promotes cancer cell proliferation and survival . Also, Fructose-1,6-bisphosphatase (FBP1), a rate-limiting
[35]
enzyme, can catalyze F-1,6-BP into fructose 6-phosphate in gluconeogenesis. This process can be repressed
by G9A mediated epigenetic modification in breast cancer cell lines. Repressed FBP1 contributes to
[36]
epithelial-mesenchymal transition transformation, promoting cancer cell metastasis . Loss of G9A initiates
HEPH expression that converts Fe into Fe . Excessive Fe will initiate cell cycle arrest machinery .
3+
3+
[37]
2+
Though, there is a lack of evidence that suggests that dysregulation of G9a affects PCa. The interaction
[38]
between G9a and NKX3.1 contributes to prostate differentiation . In addition, G9a plays as a coactivator
[23]
for PSA induction . It suggests that misregulation of G9a may possibly contribute to the generation and
progression of PCa. In conclusion, inhibition of G9a may enhance cancer treatment, making it a promising
target. The inhibition of G9a has been studied in various cancer types. CM-272, an inhibitor for both G9a
and DNMTs, activates immune-related pathway and increase the efficacy of anti-PD-1 immunotherapy
[Table 1] . Inhibition of G9a with UNC-0638 re-sensitizes pancreatic ductal adenocarcinoma tumors to
[39]
[40]
MEK inhibition and reduces drug-tolerant cells in several cancer cell lines [Table 1] .
EZH2 and histone methylation
Enhancer of zeste homolog 2 (EZH2) is the essential subunit of the polycomb repressor complex2 (PRC2)
and acts as a histone methyltransferase to catalyze tri-methylation of Lys27 on histone H3 (H3K27me3).
EZH2 is commonly known to promote the progression of diverse human cancers by H3K27me3-mediated
silencing of tumor suppressors [41,42] . However, EZH2 can also methylate target genes directly, such as
STAT3, GATA4, and Jarid2, to modulate their expression and contribute to cancer development [43-45] . In
addition to the catalytic function of EZH2 in epigenetic modification, a novel PRC2-independent role of
EZH2 as a transcriptional activator was identified by several studies, including NOTCH1, NF-κB, and Wnt
signaling [46-48] . In the development of PCa, specifically CRPC, EZH2 has been identified to function as a
transcriptional coactivator interacting with AR. This functional transfer from a transcriptional suppressor to
[49]
an activator is driven by the AKT-dependent phosphorylation of EZH2 at Serine-21 . Recently, it was
[50]
documented that EZH2 can activate AR signaling via direct binding at the AR promoter region .
According to these established molecular mechanisms contributing to ADT-resistance acquisition, our lab
has questioned whether EZH2 contributes to the resistance of ENZ in CRPC. Our lab determined that