METTL16 (Methyltransferase 16, RNA N6-Adenosine)

METTL16 overexpression conferred resistance to docetaxel and paclitaxel across multiple TNBC models, and METTL16 expression was elevated in paclitaxel-resistant cells. Surprisingly, genetic ablation of METTL16 caused profound loss of TNBC cell viability, while having only modest effects on nonmalignant mammary epithelial cells, indicating a cancer-selective dependency. Collectively, these findings define a METTL16-ABCB1 interaction that drives taxane resistance and establish METTL16 as a therapeutic target in TNBC.

Clinically, elevated ZNF460, alone or in combination with overexpression of METTL16 and SOX4, is predictive of poor prognosis. Collectively, our findings identify a novel oncogenic epitranscriptomic axis of METTL16/ZNF460/SOX4 which is involved in generating the EMT phenotype and regulating GC metastasis.

Notably, pharmacological targeting of METTL16 enhances the efficacy of multiple PIs in MM cells. These findings not only expand the functional landscape of METTL16 beyond RNA methylation, but also suggest that METTL16 represents a potential target for improving PI-based therapy in MM.

However, further in-depth studies are required to validate these findings. By comprehensively summarizing the current literature on METTL16, we provide a theoretical basis for its application as a diagnostic and prognostic marker as well as a potential therapeutic target for digestive system cancers.

Notably, targeting CDK13 with the small-molecule inhibitor 1NM-PP1 potentiates METTL16 depletion-mediated anticancer effects. Our findings establish a kinase-RNA modifier axis that links CDK13 to epitranscriptomic control of lipid metabolism, positioning the CDK13-METTL16-ACLY pathway as a promising target for precision therapies against ccRCC.

Proteomics analysis further elucidated the relationship and mechanisms among METTL16, astaxanthin, and ferroptosis, revealing significant changes in several key proteins associated with ferroptosis-related pathways, mitochondrial energy metabolism, oxidative stress, and fatty acid metabolism. This study demonstrates that astaxanthin inhibits CRC cell growth and delineates its relationship and mechanisms with METTL16 and ferroptosis, providing a new direction for CRC treatment.

Additionally, METTL16-mediated m6A modification of EEF1A1 mRNA activates the m6A-IGF2BP1 axis, resulting in increased EEF1A1 protein levels and enhanced resistance to ENZ-induced apoptosis. These findings uncover a novel UFL1-METTL16-EEF1A1 signaling pathway that drives ENZ resistance, suggesting that targeting this cascade may offer a promising therapeutic strategy for overcoming ENZ resistance in prostate cancer.

In vivo, METTL16 silencing repressed the cervical cancer tumor growth. Therefore, these findings revealed that novel m6A writer METTL16 promoted the cervical cancer tumorigenesis by targeting FTH1-dependent ferroptosis, which providing distinct insights for cervical cancer.

This review provides a detailed examination of METTL16's functions and regulatory mechanisms in cancer, emphasizing its m6A-dependent and m6A-independent roles in regulating RNA stability and function. Furthermore, it proposes that targeting METTL16 represents a promising avenue for cancer therapy.

LINC01940 is a cancer-testis lncRNA that promotes GC progression and cisplatin resistance by enhancing ribosome biogenesis via the METTL16/IGF2BP3-TAF15-NOL11 axis. These findings suggest its potential as a prognostic biomarker and therapeutic target in GC.