N6‑methyladenosine (m6A) is the most prevalent internal RNA modification, dynamically regulating RNA metabolism and cancer biology. In colorectal cancer (CRC), dysregulated m6A controls tumor growth, metastasis, immune evasion, and therapy resistance. This review integrates evidence on m6A machinery, its coordination with oncogenic signaling (Wnt/β‑catenin, PI3K/Akt, MAPK, p53) and metabolic pathways (glucose, amino acid, lipid), and translational implications. Key regulators include writers (METTL3, METTL14), erasers (FTO, ALKBH5), and readers (YTHDF, IGF2BP families). m6A‑dependent regulation of metabolic enzymes (HK2, PKM2, FASN) links epitranscriptomics to bioenergetic adaptation, positioning m6A as a central hub integrating signaling and metabolism for potential biomarker and targeted therapy development.
Introduction
m6A is a reversible modification affecting RNA stability, splicing, and translation. Dysregulated m6A impacts tumorigenesis and progression. This review summarizes m6A regulatory roles in CRC, focusing on oncogenic signaling and metabolic reprogramming.
m6A Regulatory Machinery in CRC
Writers (methyltransferases) : METTL3 (context‑dependent, suppresses/invasion via p38/ERK or promotes progression), METTL14 (suppresses stemness via SCD1), WTAP (promotes proliferation via FLNA, angiogenesis via VEGFA), ZC3H13 (inhibits proliferation via Ras‑ERK), ZCCHC4 (promotes chemoresistance).
Erasers (demethylases) : FTO (promotes proliferation, glycolysis via PKM2/HK2); ALKBH5 (dual functions – promotes progression via NEAT1, inhibits metastasis, modulates PD‑L1, suppresses lipid metabolism via FABP5).
Readers : IGF2BP1/2/3 (stabilize mRNAs like MYC, FZD6, HK2; IGF2BP1 suppresses CD8⁺ T‑cell cytotoxicity; IGF2BP2 promotes glycolysis; IGF2BP3 is a poor prognosis marker); YTHDF1 (promotes translation, reduces cisplatin sensitivity via GLS); YTHDF2 (regulates ferroptosis via GPX4).
m6A‑Regulated Oncogenic Signaling
Wnt/β‑catenin : YTHDF1 enhances translation of FZD9/WNT6, activating Wnt signaling and tumor growth.
PI3K/Akt : Reduced m6A methylation activates PI3K/Akt, enhancing proliferation. m6A‑related ceRNA networks affect ferroptosis and drug sensitivity.
MAPK : Reduced METTL3 activates ERK/p38; WTAP promotes angiogenesis via VEGFA m6A methylation.
p53 : METTL3 stabilizes p53 mRNA; silencing METTL3 activates p53 pathway, resensitizing CRC cells to chemotherapy.
m6A‑Regulated Metabolic Pathways
Glucose metabolism : IGF2BP2 stabilizes ZFAS1/OLA1, increasing glycolysis. FTO/ALKBH5 downregulation activates FOXO via HK2 m6A methylation. METTL3 stabilizes HK2/SLC2A1, promoting glycolysis.
Amino acid metabolism : m6A regulates GLS1, SHMT, IDO1, influencing energy, biosynthesis, and immune evasion. Linc00266‑1‑encoded RBRP stabilizes c‑Myc via IGF2BP1.
Lipid metabolism : ALKBH5 enhances FABP5, reducing FASN and lipid accumulation, inhibiting mTOR. FASN promotes progression and suppresses NK immunity. Secondary bile acids activate TGR5/STAT3/KLF5.
Crosstalk Between Metabolism and Signaling
m6A‑mediated metabolic rewiring indirectly shapes signaling: glycolysis activates PI3K/Akt; lipid metabolism modulates mTOR and Wnt/β‑catenin via acetyl‑CoA. m6A acts as a molecular bridge connecting metabolism with oncogenic networks.
Limitations and Future Directions
Most data from cell/xenograft models; validation with organoids, spatial transcriptomics, and cohorts needed.
Spatiotemporal dynamics and functional redundancy among regulators remain unclear.
m6A‑targeted therapies (e.g., METTL3 inhibitor STM2457) show preclinical promise but need solid tumor validation.
Future work should map the m6A epitranscriptome, elucidate immune‑metabolism interactions, and develop selective therapeutics with biomarkers.
Conclusions
m6A is a central regulator in CRC, integrating signaling (Wnt, PI3K/Akt, MAPK, p53) and metabolic pathways (glucose, amino acid, lipid). Targeting the m6A machinery (e.g., METTL3 inhibition) and using m6A‑based biomarkers (IGF2BP3, YTHDF1) hold promise for precision CRC management. Further translational research is needed.
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The study was recently published in the Cancer Screening and Prevention .
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Cancer Screening and Prevention
m6A RNA Modification in Colorectal Cancer: Regulatory Roles, Oncogenic Signaling, and Metabolic Pathways
29-Mar-2026