In a recent review published in Genes & Diseases, researchers from Jinan University, Guangzhou Medical University, Cedars-Sinai Medical Center, and Jinan-Puhua Joint Laboratory provide a comprehensive overview of the methyltransferase-like 16 (METTL16) protein, an independent N6-methyladenosine (m6A) "writer" that plays a critical role in the development and progression of various malignancies.

Mechanistically, METTL16 functions via both m6A-dependent and m6A-independent pathways. In the former, it catalyzes the methylation of specific RNA substrates (notably U6 snRNA and MAT2A mRNA), thereby altering mRNA splicing, stability, and translation, and also by regulating SAM (S-adenosylmethionine) homeostasis, which indirectly influences global RNA methylation. In the m6A-independent pathway, METTL16 modulates gene expression through direct binding to specific RNA sequences and interactions with proteins involved in translation machinery, such as eIF4E2, thereby affecting cellular processes.

METTL16 is regulated at multiple levels, including transcriptional control by hypoxia-related factors and other transcription factors, post-translational modifications, and genetic alterations that influence its expression and activity. METTL16 exerts both oncogenic and tumor-suppressive functions depending on the specific cancer context. For example, it suppresses ovarian cancer via the MALAT1–β-catenin axis and pancreatic adenocarcinoma through cell cycle and immune regulation, while promoting breast cancer proliferation by stabilizing FBXO5 mRNA and colorectal cancer growth via modulating glycolytic enzymes.

Aberrant METTL16 expression is associated with various aspects of tumorigenesis, including proliferation, invasion, metastasis, metabolic adaptation, apoptosis, autophagy, immune evasion, and chemotherapeutic resistance across multiple cancer types, including bladder, lung, colorectal, breast, ovarian, pancreatic, and acute myeloid leukemia.

METTL16 serves as a versatile epitranscriptomic regulator that modulates tumorigenesis by integrating into key oncogenic pathways, metabolic processes, and immune networks. It regulates the stability and translation of critical transcripts such as DVL2 and p21, thereby influencing the Wnt/beta-catenin pathway and cell cycle progression. METTL16 dictates tumor cell fate by controlling specialized death pathways—promoting ferroptosis evasion via GPX4 stabilization while facilitating cuproptosis through FDX1 upregulation.

Furthermore, METTL16 dictates the tumor microenvironment by modulating PD-L1 expression and immune cell infiltration. In low-grade gliomas, it negatively correlates with CD8+ T-cell infiltration, suggesting a role in driving a "cold," immunosuppressive phenotype, thereby highlighting its potential as both a prognostic biomarker and a target for precision immunotherapy.
Targeting METTL16's methyltransferase activity either through small-molecule inhibitors or PROTAC-mediated degradation represents a promising strategy for precision oncology.

In conclusion, this study summarizes the role of METTL16 in regulating the cancer epitranscriptome. Although it represents a compelling therapeutic target, comprehensive in vivo investigations are needed to understand its complex and intricate regulatory networks and confirm the clinical safety and efficacy of METTL16-directed therapeutic interventions.

Reference

Title of the original paper: METTL16 in cancer: Roles and regulatory mechanisms

Journal : Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI : https://doi.org/10.1016/j.gendis.2025.101758


Funding Information:

• National Natural Science Foundation of China (No. 82370167)
• Guangdong Basic and Applied Basic Research Foundation of China (No. 2023A1515012118)
• Guangzhou Municipal Science and Technology Project (China) (No. 2025A03J3231)

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