Switching from messenger RNAs to noncoding RNAs, METTL3 is a novel colorectal cancer diagnosis and treatment target

Abstract

N6-methyladenosine (m6A) modification, one of the most prevalent RNA epigenetic modifications in eukaryotes, constitutes over 60% of all RNA methylation modifications. This dynamic modification regulates RNA processing, maturation, nucleocytoplasmic transport, translation efficiency, phase separation, and stability, thereby linking its dysregulation to diverse physiological and pathological processes. METTL3, a core catalytic component of the methyltransferase complex responsible for m6A deposition, is frequently dysregulated in diseases, including colorectal cancer (CRC). Although METTL3's involvement in CRC pathogenesis has been documented, its precise molecular mechanisms and functional roles remain incompletely understood. METTL3 mediates CRC progression-encompassing proliferation, invasion, drug resistance, and metabolic reprogramming-through m6A-dependent modulation of both coding RNAs and noncoding RNAs. Its regulatory effects are primarily attributed to interactions with key signaling pathways at multiple stages of CRC development. Emerging evidence highlights METTL3 as a promising biomarker for CRC diagnosis and prognosis, as well as a potential therapeutic target. By synthesizing recent advances in METTL3 research within CRC, this review provides critical insights into novel strategies for clinical diagnosis and targeted therapy.

Keywords: Biomarker; Colorectal cancer; Epigenetics; METTL3; N6-methyladenosine; Targeted treatment.

Figure 1

Dynamic regulation of N6-methyladenosine modification. N6-methyladenosine (m6A) writers, erasers, and readers control the process of m6A modification. Writers (METTL3, METTL14, WTAP, METTL5, and METTL16) catalyze m6A deposition, erasers (FTO and ALKBH5) remove methyl groups, and readers (YTHDF1/YTHDF2/YTHDF3, YTHDC1/YTHDC2/YTHDC3, IGF2BP1/IGF2BP2/IGF2BP3) decode these marks to influence RNA stability, messenger RNA translation, RNA degradation, translocation, RNA splicing, structure switching, and primary microRNA processing. M6A: N6-methyladenosine.

Figure 2

METTL3-mediated N6-methyladenosine modification of messenger RNAs in colorectal cancer. METTL3 participates in colorectal cancer (CRC) by regulating N6-methyladenosine modification of messenger RNAs (mRNAs) involved in proliferation, invasion and metastasis, metabolic disorder, and resistance of CRC cells. Every mRNA was detailed with a name. HK2: Hexokinase 2; GLUT1: Glucose transporter type 1; mRNAs: Messenger RNAs; m6A: N6-methyladenosine; CRC: Colorectal cancer.

Figure 3

METTL3-mediated N6-methyladenosine modification of noncoding RNAs in colorectal cancer. METTL3 participates in colorectal cancer (CRC) by regulating N6-methyladenosine modification of noncoding RNAs (ncRNAs) involved in proliferation, invasion and metastasis, metabolic disorder, and resistance of CRC cells. Each ncRNA was detailed with a name. ncRNAs: Noncoding RNAs; m6A: N6-methyladenosine; CRC: Colorectal cancer.

Figure 4

Expression and function analysis of METTL3. A: Pan-cancer analysis of METTL3; B: Expression of METTL3 in colon adenocarcinoma (COAD); C: METTL3 expression across COAD stages; D: Prognosis of METTL3 in COAD; E: Integration of the top 150 METTL3 target genes; F: Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of METTL3 targets; G: Drug-protein interaction analysis of Patupilone, YM-155, KIN001-266, and METTL3 in prostate adenocarcinoma. TCGA: The Cancer Genome Atlas; TPM: Transcripts per million; BLCA: Bladder urothelial carcinoma; BRCA: Breast invasive carcinoma; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL: Cholangiocarcinoma; COAD: Colon adenocarcinoma; ESCA: Esophageal carcinoma; GBM: Glioblastoma multiforme; HNSC: Head and neck squamous cell carcinoma; KICH: Kidney chromophobe; KIRC: Kidney renal clear cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; LIHC: Liver hepatocellular carcinoma; LUAD: Lung adenocarcinoma; LUSC: Lung squamous cell carcinoma; PAAD: Pancreatic adenocarcinoma; PRAD: Prostate adenocarcinoma; PCPG: Pheochromocytoma and paraganglioma; READ: Rectum adenocarcinoma; SARC: Sarcoma; SKCM: Skin cutaneous melanoma; STAD: Stomach adenocarcinoma; UCEC: Uterine corpus endometrial carcinoma; KEGG: Kyoto Encyclopedia of Genes and Genomes.