METTL3 drives oral cancer by blocking tumor-suppressing gene

“[…] we report that METTL3, an oncogene regulates the expression of SMAD4, a tumor-suppressor via miR-146a-5p, thus unveiling a novel regulatory axis of METTL3/miR-146a-5p/SMAD4 in OSCC, which can potentially have therapeutic implications.”

BUFFALO, NY – May 9, 2025 – A new research paper was published in Oncotarget, Volume 16, on May 8, 2025, titled “METTL3 promotes oral squamous cell carcinoma by regulating miR-146a-5p/SMAD4 axis.”

In this study, researchers Jayasree Peroth Jayaprakash, Pragati Karemore, and Piyush Khandelia from the Birla Institute of Technology and Science, India, discovered that a molecule called METTL3 contributes to the development and spread of oral squamous cell carcinoma (OSCC). The study shows that METTL3 increases the levels of a small RNA molecule called miR-146a-5p, which blocks SMAD4, a key tumor-suppressing gene. These findings help explain why oral cancers are difficult to treat and may offer a new target for more effective therapies.

Oral squamous cell carcinoma is a common and aggressive cancer affecting the mouth and throat. It has a high death rate, mainly due to late detection, treatment resistance, and the cancer’s ability to invade nearby tissues. In this study, the researchers focused on METTL3, an enzyme that adds chemical tags known as m6A marks to RNA, which change how genetic information is used by cells. They found that METTL3 is unusually active in OSCC cells, causing an increase in miR-146a-5p. This molecule, in turn, blocks the function of SMAD4, which helps control how cells grow and die in our bodies.

“METTL3, the primary m6A RNA methyltransferase, is significantly upregulated in OSCC cells leading to increased global m6A levels.”

When METTL3 was reduced or chemically blocked, miR-146a-5p levels dropped and SMAD4 levels increased. This shift slowed the growth of cancer cells, increased their death, and made them less likely to spread. When researchers reintroduced miR-146a-5p or lowered SMAD4 levels again, the cancer-promoting behavior returned. These results show that the METTL3–miR-146a-5p–SMAD4 pathway plays a key role in OSCC.

The findings open up new possibilities for treatment. Drugs that block METTL3 or miR-146a-5p or that restore SMAD4 could slow or stop tumor growth. One such drug, STM2457, which targets METTL3, has already shown promise in lab studies. As research progresses, targeting this molecular pathway may offer a new strategy in treating OSCC.

This discovery improves our understanding of how OSCC develops and avoids the body’s defenses. By interfering with this newly discovered pathway, future treatments may become more successful, improving survival rates and quality of life for people with this disease.

Continue reading: DOI: https://doi.org/10.18632/oncotarget.28717

Correspondence to: Piyush Khandelia – piyush.khandelia@hyderabad.bits-pilani.ac.in 

Keywords: cancer, oral cancer, m6A RNA methylation, METTL3, miR-146a-5p, SMAD4

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