The interplay between m6A modification and non-coding RNA in cancer stemness modulation: mechanisms, signaling pathways, and clinical implications

Abstract

Cancer stemness, mainly consisting of chemo-resistance, radio-resistance, tumorigenesis, metastasis, tumor self-renewal, cancer metabolism reprogramming, and tumor immuno-microenvironment remodeling, play crucial roles in the cancer progression process and has become the hotspot of cancer research field in recent years. Nowadays, the exact molecular mechanisms of cancer stemness have not been fully understood. Extensive studies have recently implicated that non-coding RNA (ncRNA) plays vital roles in modulating cancer stemness. Notably, N6-methyladenosine (m6A) modification is of crucial importance for RNAs to exert their biological functions, including RNA splicing, stability, translation, degradation, and export. Emerging evidence has revealed that m6A modification can govern the expressions and functions of ncRNAs, consequently controlling cancer stemness properties. However, the interaction mechanisms between ncRNAs and m6A modification in cancer stemness modulation are rarely investigated. In this review, we elucidate the recent findings on the relationships of m6A modification, ncRNAs, and cancer stemness. We also focus on some key signaling pathways such as Wnt/β-catenin signaling, MAPK signaling, Hippo signaling, and JAK/STAT3 signaling to illustrate the underlying interplay mechanisms between m6A modification and ncRNAs in cancer stemness. In particular, we briefly highlight the clinical potential of ncRNAs and m6A modifiers as promising biomarkers and therapeutic targets for indicating cancer stemness properties and improving the diagnostic precision for a wide variety of cancers.

Integrative Analyses of m6A Regulators Identify that METTL3 is Associated with HPV Status and Immunosuppressive Microenvironment in HPV-related Cancers

“…Recent studies indicated that m6A modification has a close relationship with tumor immune microenvironment (TIME) remodeling, which could affect the development of tumors [21]. High m6A modification linked with a non-inflamed and immune-exclusion tumor microenvironment phenotype that lacked effective immune infiltration and exhibited a poorer survival rate for stroma [21,22]. The m6A regulators such as ALKBH5 and YTHDF1 had a close relation to the immune microenvironment remodeling of gliomas [23].…”

Decreased Expression of Programmed Death Ligand-L1 by Seven in Absentia Homolog 2 in Cholangiocarcinoma Enhances T-Cell–Mediated Antitumor Activity

“…The ultimate fate of m6A methylated mRNA depends on the "reader" (e.g., YTHDF1, YTHDF2, and YTHDF3) that recognizes them, affecting mRNA translation, stability, splicing, and nuclear transportation (7). Numerous m6A targets have been involved in cell tissue development and stem cell self-renewal and differentiation, circadian rhythm regulation, T-cell homeostasis, mouse fertility, postnatal development of the mouse cerebellum, innate immune response, ultraviolet-induced DNA damage response, and dendritic cell antigen presentation (8)(9)(10). However, the possible role of m6A modification in tumor-immune microenvironment and in CCA remains to be elucidated.…”

Novel insights into the interaction between N6‐methyladenosine methylation and noncoding RNAs in musculoskeletal disorders

“…METTL3 acts as an RNA marker that promotes the initiation of miRNA biogenesis by DGCR8 and Dicer. METTL3 accelerates pri‐miRNA processing and maturation via promoting the integration between DGCR8 and pri‐miRNA 119 and improves miRNA splicing by the pre‐miRNA Dicer cleavage 120 . Similar to METTL3, METTL14 can interact with DGCR8 and accelerate pri‐miRNA processing 121 .…”