**5. Conclusion and perspectives**

In this chapter, we have highlighted the pivotal contribution of epigenetic deregulation, specifically, DNA methylation, histone alterations, and miRNAs to the initiation, progression, and prognosis of CRC. We also underscored the relevance of these epigenetic mechanisms in terms of classifying CRC subtypes as well as their importance in guiding strategies for therapeutic intervention. Moreover, we emphasized the epigenetic enzymes that are involved in these aberrant pathways and presented some up-to-date findings on pre-clinical and clinical trials of epigenetic drugs used as single agents or in combination with conventional anticancer agents in CRC. Furthermore, mounting evidence demonstrates that epigenetic drugs are also capable of altering the immunogenicity of the CRC microenvironment and creating opportunities for potentiating the effects of immune checkpoint inhibitors.

Understandably, drugs targeting the cancer epigenome are also plagued with major challenges including lack of specificity, toxicity, and short half-life. Fortunately, these challenges have facilitated re-evaluation of the dosing and formulation strategies for epigenetic drugs, leading to superior therapeutic drugs with lower toxic profiles. Another underexplored avenue includes targeting less commonly manipulated epigenetic mechanisms such as the use of miRNA mimics [147]. Furthermore, in light of the advent of personalized therapies, more intricate studies are also needed to elucidate the relationship between individual driver genetic mutations and epigenetic alterations, thus providing a pathway-driven basis for developing selective therapeutic strategies. This may call for a more stringent control of gene expression in CRC cells via selective targeting of epigenetic regulatory

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*Epigenetic Biomarkers and Their Therapeutic Applications in Colorectal Cancer*

enzymes. This includes the prospects of CRISPR/Cas9/Cas13-based genome and RNA editing, which may provide validated starting points for further development

This publication is made possible, in part, with support from the Indiana Clinical and Translational Sciences Institute (CTSI) funded from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (to TL), V foundation Kay Yow Cancer Fund (Grant 4486242 to TL), NIH-NIGMS Grant (#1R01GM120156-01A1 (to TL), and 100 VOH Grant (#2987613 to TL), as well as NIH-NCI Grant (#1R03CA223906-01).

APAK ATM and p53-associated KZNF protein

BET bromodomain and extra-terminal motif

CDKN2A/p16INK4a cyclin-dependent kinase inhibitor 2A

CRABP1 cellular retinoic acid binding protein 1

DOT1L disruptor of telomeric silencing 1-like

EMT epithelial-to-mesenchymal transition

FDA Food and Drug Administration

CIMP CpG island methylator phenotype

DAP-kinase death-associated protein kinase 1

ASC/TMS1 or PYCARD apoptosis-associated speck-like protein contain

BRAF B-Raf proto-oncogene, serine/threonine kinase CACNA1G calcium voltage-gated channel subunit alpha1 G CARM1 coactivator-associated arginine methyltransferase 1

APC adenomatous polyposis coli

ing a CARD

BMI body mass index

CENP-E centromere protein E

CRC colorectal cancer

CIN chromosomal instability COX-2 cyclooxygenase-2

DNMT DNA methyltransferase DNMT3A DNA methyltransferase 3A

E2F1 E2F transcription factor 1 Eg5 kinesin 5 family member

GATA4 GATA-binding protein 4 HAT histone acetyltransferase HDAC histone deacetylase HDM histone demethylase

HIC1 hypermethylated in cancer 1 HKMT histone lysine methyltransferase HKMTs histone lysine methyltransferases

hMOF human males absent on the first HMT histone methyltransferase

hMLH1 human mutL homolog 1

EZH2 enhancer of zeste 2

5-FU 5-fluorouracil

*DOI: http://dx.doi.org/10.5772/intechopen.82572*

towards novel CRC therapeutic agents [148].

**Acknowledgements**

**Abbreviations**

*Epigenetic Biomarkers and Their Therapeutic Applications in Colorectal Cancer DOI: http://dx.doi.org/10.5772/intechopen.82572*

enzymes. This includes the prospects of CRISPR/Cas9/Cas13-based genome and RNA editing, which may provide validated starting points for further development towards novel CRC therapeutic agents [148].
