The collaborative epitranscriptome: bidirectional crosstalk between m6A methylation and noncoding RNAs in cancer pathogenesis and precision therapy.

Abstract

Altered post-transcriptional regulation contributes to cancer development and treatment resistance. N6-methyladenosine (m6A) modification and noncoding RNAs are closely connected within this process and can regulate one another in both directions. This review summarizes the m6A regulatory system, the biological characteristics of major ncRNA classes, and the mechanisms through which m6A and ncRNAs interact in cancer. m6A can affect ncRNA biogenesis, stability, localization, protein binding, and translation, whereas ncRNAs can alter the expression or activity of m6A writers, erasers, and readers and influence their interactions with specific RNA targets. The effects of these pathways vary with the RNA involved, the modified site, the associated proteins, and the cellular context, which helps explain why similar changes in the m6A machinery can produce different outcomes in different tumors. m6A-ncRNA interactions have been associated with tumor progression, metabolic adaptation, regulated cell death, immune regulation, and response to anticancer treatment. Several ncRNAs involved in these pathways have also been linked to prognosis, recurrence, or treatment response in patient cohorts. Experimental studies have begun to examine therapeutic strategies based on ncRNA inhibition or restoration and, in a smaller number of cases, direct manipulation of defined m6A events. The review also considers the clinical evidence for these pathways and the practical challenges that need to be addressed before they can be more widely explored as biomarkers or therapeutic targets.