**2.1 Epigenetic enzymes implicated in cancer**

The dysregulation of epigenetic enzymes is one of the chief contributors to cancer development and progression. Several cancers are accompanied by significantly altered DNA methylation status, and this has been shown to serve as a diagnostic and prognostic marker [40]. The resulting imbalance in gene expression is mainly caused by hypomethylation of oncogenic genes or hypermethylation of tumor-suppressive genes. Thus, inhibiting DNA methyltransferase and/or DNA demethylase is a promising therapeutic strategy for many of these cancers. For example, in breast cancer models, the inhibition of DNMT exerts reduced cellular proliferation, migration, and anchorage-independent growth activity and potentiates anti-cancer immunity [41, 42]. Similarly, inhibiting DNMT sensitizes non-small cell lung cancer (NSCLC) to ionizing radiation and a potent targeted therapeutic poly (ADP-ribose) polymerase (PARP) inhibitors [43]. The overexpression of DNMT, particularly DNMT3Ab, in gastric cancer facilitates the epithelial to mesenchymal transition (EMT)-related metastasis and correlates with poor prognosis in gastric cancer patients [44]. Aberrant gene silencing or activation caused by deregulated DNMTs and TETs have also been widely reported in renal, colorectal, brain, pancreatic, bladder, prostate, and other hematological cancers [45]. Among the genes that are implicated in DNA methylation dysregulation include but are not limited to retinoblastoma tumor-suppressor gene (Rb), breast cancer susceptibility gene 1 (BRCA1), cyclin-dependent kinase inhibitor 2A (CDKN2A), and microRNAs [46]. Collectively, the atypical expression of some of these genes leads to genomic instability and uncontrolled cell cycle progression.

Likewise, the PTM of histone tails at gene promoters and on specific residues of non-histone proteins promote different cancer hallmarks. HATs and HDACs regulate acetylation patterns on several proteins and serve as co-activators/repressors of transcription factors implicated in cancer [35, 36]. For instance, in prostate cancer tissues, CBP/p300 transcript levels are significantly high. They potentiate the constitutive activation of androgen receptor signaling in castration-resistant prostate cancer, leading to increased tumor growth [47]. Moreover, the overexpression of the human MYST1, a member of HATs, promotes acetylation of Nrf2 at K588, thereby aiding the tolerance of replication stress in NSCLC [48]. The erasure of acetylation marks is also an important driver of cancer progression. HDACs are typically overexpressed and result in the silencing of key tumor suppressor genes. Particularly, in breast cancer, the use of HDAC inhibitors has shown remarkable potential in preventing hormonal-based therapy resistance through the restoration of epigenetic alterations [49]. A separate review has extensively delineated the role of HDACs in altering

gene expression in cancer through chromatin remodeling and transcription factors regulation [50]. Also, the methylation and demethylation of histone and non-histone substrates have a diverse function in carcinogenesis. For example, the high expression of human telomerase reverse transcriptase (hTERT) observed in many cancers is associated with the heavily trimethylated histone H3K4. H3K4 is a known substrate of SMYD3, a KMT that is commonly overexpressed in cancers [51]. Also, different KMTs such as KMT2A and Dot1-like protein (DOT1L) fuse with proto-oncogenes to promote the progression of hematological malignancies [38]. Another overly expressed KMT in cancer, enhancer of zeste homolog 2 (EZH2) catalyzes the methylation of H3K27 and genes like p16, NF-κB, CDK4, Ras, β-catenin to further different tumors' survival [52]. Similarly, overexpression of KDMs, such as LSD1, LSD2, and KDM5B, cause increased tumor growth and chemoresistance *via* aberrant demethylation of H3K4 in prostate cancer, breast cancer, NSCLC, and hepatocellular carcinoma [53]. A growing number of studies have also documented the widespread role of the known human PRMTs in cancers. The overexpression of PRMTs has been found in breast, prostate, colon, bladder, ovarian, skin, and gastric cancers, including various hematological malignancies [54]. Notably, our group extensively studies PRMT5, and we discovered that its overexpression in pancreatic and colorectal cancer results in increased cell growth, migration, and anchorage-independent growth *via* dimethylation of R30 of NF-κB subunit, p65 [55, 56]. We also revealed that PRMT5 oncogenic role in colorectal cancer potentiates NF-κB signaling through dimethylation of R205 of Y-box binding protein 1 (YBX1) [57]. Taken together, the deregulation of epigenetic enzymes has an entrenched and indisputable role in the etiology and progression of many cancers, making them promising therapeutic targets.
