Mechanisms and clinical landscape of N6-methyladenosine (m6A) RNA modification in gastrointestinal tract cancers

Abstract

Epigenetics encompasses reversible and heritable chemical modifications of non-nuclear DNA sequences, including DNA and RNA methylation, histone modifications, non-coding RNA modifications, and chromatin rearrangements. In addition to well-studied DNA and histone methylation, RNA methylation has emerged as a hot topic in biological sciences over the past decade. N6-methyladenosine (m6A) is the most common and abundant modification in eukaryotic mRNA, affecting all RNA stages, including transcription, translation, and degradation. Advances in high-throughput sequencing technologies made it feasible to identify the chemical basis and biological functions of m6A RNA. Dysregulation of m6A levels and associated modifying proteins can both inhibit and promote cancer, highlighting the importance of the tumor microenvironment in diverse biological processes. Gastrointestinal tract cancers, including gastric, colorectal, and pancreatic cancers, are among the most common and deadly malignancies in humans. Growing evidence suggests a close association between m6A levels and the progression of gastrointestinal tumors. Global m6A modification levels are substantially modified in gastrointestinal tumor tissues and cell lines compared to healthy tissues and cells, possibly influencing various biological behaviors such as tumor cell proliferation, invasion, metastasis, and drug resistance. Exploring the diagnostic and therapeutic potential of m6A-related proteins is critical from a clinical standpoint. Developing more specific and effective m6A modulators offers new options for treating these tumors and deeper insights into gastrointestinal tract cancers.

Keywords: Clinical applications; Expression level; Gastrointestinal tract cancers; Mechanism; m6A.

Fig. 1

Overview of the involvement of m6a in several types of common gastrointestinal tract cancers. The dysregulation of m6A regulators plays essential roles in gastrointestinal tract cancers by impacting various biological processes such as cell proliferation, migration, invasion, and metabolic reprogramming

Fig. 2

The main functions and mechanism of m6A in several types of common gastrointestinal tract cancers. Various m6A regulators modulate expression levels of cancer-related genes by influencing RNA stability, post-transcriptional modifications, and translation efficiency, thus participating in the occurrence and development of gastrointestinal tract cancers

Fig. 3

m6A modification holds promise in gastrointestinal tract cancers for clinical diagnosis, prognosis prediction, and treatment guidance. Kaplan–Meier survival and receiver operating characteristic curves confirmed the reliability of abnormal m6A levels as diagnostic indicators. Univariate and multivariate regression models support m6A as an independent prognostic indicator. Research on m6A regulation mechanisms in the progression of digestive tract tumors suggests that targeting abnormal m6A levels improves chemotherapy and radiotherapy resistance. Modulating m6A levels enhances the efficacy of immunotherapy, improving patient survival rates. Furthermore, targeted drug delivery systems achieve significant anticancer effects