DNA, RNA, and histone methylation regulation enzymes and their crosstalk in colorectal carcinogenesis and progression: a review of molecular mechanisms, clinical implications, and future perspectives.

Colorectal cancer (CRC) ranks among the most common malignant cancers of the digestive system, and its initiation and progression are closely related to both genetic and epigenetic mechanisms. Three major forms of modifications, viz. DNA methylation, RNA m6A methylation, and histone methylation, play important roles in regulating gene expression at various stages of transcription and translation. These methylation processes are dynamic and reversible, relying on the functions of methyltransferases, demethylases, and methylation-binding proteins. Extensive studies have shown that DNA, RNA m6A, and histone methylation significantly impact multiple pathological and physiological processes in CRC, including carcinogenesis, recurrence, metastasis, resistance to both radiotherapy and chemotherapy, as well as immune regulation. Advances in high-throughput sequencing and laboratory techniques have facilitated the identification of methylation regulation enzymes with aberrant expression at the DNA, RNA, and protein levels, revealing their clinical potential for early diagnosis and treatment of CRC. The upstream regulatory mechanisms controlling these methylation regulation enzymes are crucial for understanding alterations in methylation patterns. Current evidence identifies several key mechanisms, including posttranslational modifications, epigenetic regulation, and genetic alterations, which collectively influence the expression, activity, and stability of methyltransferases, demethylases, and binding proteins. These mechanisms thereby modulate the dynamic methylation landscape across various biological contexts. Furthermore, the complex crosstalk among DNA, RNA m6A, and histone methylation is increasingly being elucidated, highlighting a need for further investigation in CRC. In this review, we systematically summarize the molecular mechanisms, clinical applications, and crosstalk involving DNA methylation, RNA m6A methylation, and histone methylation, along with their related enzymes in the development of CRC. This review aims to provide new insights and directions that underscore the significant role of epigenetic methylation modifications and their associated enzymes in CRC.