Oral squamous cell carcinoma (OSCC) is an aggressive disease that has substantial impacts on global health. RNA N6-Methyladenosine (m6A) modification is an emerging player in the posttranscriptional regulation of gene expression. m6A is a reversible modification and regulated by specific enzymes. METTL3 is a master regulator enzyme of m6A modification and its dysregulation is strongly associated with different types of cancer including OSCC. Here, we describe the development of STM2457, a new class of highly potent and selective, small-molecule inhibitor of METTL3 for OSCC treatment.
The expression and clinical implication of METTL3 were investigated in OSCC patients. The underlying mechanisms of METTL3 in OSCC were investigated using OSCC cell lines. Efficacy analysis of STM2457 against OSCC was elucidated in OSCC cell lines and patient-derived OSCC organoids.
The m6A levels and METTL3 expression were increased in OSCC patients and OSCC cell lines. Clinically, increased expression of METTL3 indicated poor survival and adverse pathological features. Functionally, knockdown of the METTL3 gene in OSCC cells dramatically inhibited cellular proliferation, invasion and colony formation. Furthermore, STM2457 treatment exerted potential anti-tumorigenic and anti-metastatic activity in OSCC cells and patient-derived OSCC organoids through reduced m6A level, cell proliferation, cell viability and increased apoptosis.
Thus, we propose METTL3 inhibition as a novel and potent therapeutic option for OSCC.
Legal entity responsible for the study
Indian Council of Medical Research (DHR-GIA, 2020-9530 to A. Paramasivam), Government of India.
All authors have declared no conflicts of interest.