International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 227-238 http://medscipublisher.com/index.php/ijmms 229 3.2.2 Histone modifications Histone modifications, including acetylation, methylation, phosphorylation, and ubiquitination, play a critical role in regulating chromatin structure and gene expression. These modifications can either activate or repress gene transcription. In cancer, dysregulated histone modifications contribute to the aberrant expression of genes involved in cell cycle regulation, apoptosis, and metastasis. Targeting histone-modifying enzymes has emerged as a promising therapeutic strategy (Sharma et al., 2010; Berdasco and Esteller, 2010; Cheng et al., 2019). 3.2.3 Non-Coding RNAs Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are key regulators of gene expression. They can modulate gene expression at the transcriptional and post-transcriptional levels. In cancer, altered expression of ncRNAs can lead to the dysregulation of pathways involved in cell proliferation, apoptosis, and metastasis. miRNAs, in particular, have shown potential as biomarkers and therapeutic targets in various cancers, including CRC (Okugawa et al., 2015; Jung et al., 2020; Bhol et al., 2020). 3.3 Epigenetic alterations in cancer development Epigenetic alterations are integral to the initiation and progression of cancer. These changes can occur early in carcinogenesis and affect virtually all key cancer-associated pathways. For example, in CRC, the accumulation of epigenetic changes, such as DNA methylation and histone modifications, drives the transformation of normal colonic epithelium into adenomas and invasive adenocarcinomas. The reversibility of epigenetic modifications makes them attractive targets for cancer therapy, with several epigenetic drugs already approved for clinical use (Sharma et al., 2010; Dawson and Kouzarides, 2012; Kelly and Issa, 2017; Jung et al., 2020). Epigenetic therapies aim to "reset" the abnormal epigenetic landscape of cancer cells, thereby restoring normal gene function and inhibiting tumor growth. The development of inhibitors targeting DNA methyltransferases and histone deacetylases has shown promise in preclinical and clinical studies, highlighting the potential of epigenetic interventions in cancer treatment (Dawson and Kouzarides, 2012; Cheng et al., 2019). 4 DNA Methylation: Mechanisms and Functions 4.1 Overview of DNA methylation DNA methylation is a crucial epigenetic modification involving the addition of a methyl group to the fifth carbon atom of cytosine residues, primarily within CpG dinucleotides. This process is essential for various biological functions, including embryonic development, X-chromosome inactivation, and genomic imprinting (Uysal et al., 2015). DNA methylation patterns are established and maintained by DNA methyltransferases (DNMTs) and can be dynamically regulated by demethylation processes mediated by ten-eleven translocation (TET) enzymes (Seiler et al., 2018; Shekhawat et al., 2021). 4.2 Enzymes Involved in DNA Methylation and Demethylation 4.2.1 DNA methyltransferases (DNMTs) The DNMT family includes DNMT1, DNMT3A, DNMT3B, DNMT2, and DNMT3L. DNMT1 is primarily responsible for maintenance methylation, ensuring the propagation of methylation patterns during DNA replication by targeting hemimethylated DNA (Uysal et al., 2015; Seiler et al., 2018). DNMT3A and DNMT3B are de novo methyltransferases that establish new methylation patterns on unmethylated DNA, playing critical roles in early development and cellular differentiation (Uysal et al., 2015). DNMT3L, although catalytically inactive, assists DNMT3A and DNMT3B in de novo methylation (Uysal et al., 2015). DNMT2, on the other hand, primarily methylates tRNA rather than DNA (Uysal et al., 2015). 4.2.2 Ten-Eleven translocation (TET) enzymes TET enzymes (TET1, TET2, and TET3) are involved in the active demethylation of DNA. They catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which can be further oxidized to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) (Seiler et al., 2018; Shekhawat et al., 2021). These oxidized forms can be recognized and excised by thymine DNA glycosylase (TDG), leading to DNA demethylation and gene reactivation (Zhang et al., 2013; Seiler et al., 2018; Shekhawat et al., 2021). TET enzymes
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