Methyltransferase-like 3-induced N6-methyladenosine upregulation promotes oral squamous cell carcinoma by through p38

Oral squamous cell carcinoma (OSCC), a main type of squamous cell cancer, is associated with considerable morbidity and mortality. Recent reports suggested methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) modification to be an essential regulator in the fate determination of stem cells. However, the functional significance of METTL3 in OSCC remains largely unknown.

METTL3 expression was examined in OSCC patient samples, followed by correlation analysis against clinical tumor features. Functional assays, such as assessment of surface marker expression, colony forming, BrdU incorporation, tumor xenograft assay, and m6A dot blot, were conducted to study the impact of METTL3 knockdown (KD) in OSCC cells.

High METTL3 expression was positively correlated with more severe clinical features of OSCC tumors. METTL3 KD caused impairment of stem-like capacities in OSCC cells, such as tumorigenicity in vivo and colony-forming ability in vitro. Furthermore, METTL3-KD and cycloleucine, a methylation inhibitor, decreased m6A levels and down-regulated p38 expression in OSCC cells. On the contrary, the impaired cell proliferation capacity of OSCC cells after METTL3-KD was restored by exogenous expression of p38.

Our findings identified m6A methyltransferase METTL3 as a key element in the regulation of tumorigenesis in OSCC.