METTL3 promotes oral squamous cell carcinoma by regulating miR-146a-5p/SMAD4 axis

Sep 24, 2026

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N6-methyladenosine (m6A) is a reversible RNA modification shaping tumor epitranscriptomic gene regulation in oral squamous cell carcinoma (OSCC). METTL3 is markedly upregulated in OSCC cells, increasing global m6A and promoting oncogenic miRNA biogenesis. The study identifies miR-146a-5p as a METTL3-regulated oncomiR: METTL3 depletion or catalytic inhibition reduces miR-146a-5p while accumulating pri-miR-146a. SMAD4 is confirmed as a miR-146a-5p target, and its depletion worsens oncogenic traits, whereas overexpression counteracts them. Gene dysregulation supports METTL3 involvement in SMAD4-dependent TGF-β signaling, revealing the METTL3/miR-146a-5p/SMAD4 axis as a therapeutic target.

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Abstract

Introduction

[www.oncotarget.com](www.oncotarget.com) Oncotarget, 2025, Vol. 16, pp: 291-309 Research Paper METTL3 promotes oral squamous cell carcinoma by regulating miR-146a-5p/SMAD4 axis Jayasree Peroth Jayaprakash 1, Pragati Karemore 1 and Piyush Khandelia 1 1 Laboratory of Molecular Medicine, Department of Biological Sciences, Birla Institute of Technology and Science, Pilani Hyderabad Campus, Hyderabad 500078, India Correspondence to: Piyush Khandelia, [email](email: piyush.khandelia@hyderabad.bits-pilani.ac.in)[: piyush.khandelia@hyderabad.bits-pilani.ac.in](email: piyush.khandelia@hyderabad.bits-pilani.ac.in)[ ](email: piyush.khandelia@hyderabad.bits-pilani.ac.in)[Keywords](Keywords: oral cancer)[: oral cancer](Keywords: oral cancer); m6A RNA methylation; METTL3; miR-146a-5p; SMAD4 Received: January 03, 2025 Accepted: April 17, 2025 Published: May 08, 2025 Copyright: © 2025 Jayaprakash et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4 .0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT N6-methyladenosine (m6A), one of the most prominent and reversible internal modifications of eukaryotic RNAs, has emerged as a critical regulator of gene expression in various cancers including oral squamous cell carcinoma (OSCC), wherein it shapes the tumor-specific epitranscriptomic gene-regulatory networks. METTL3, the primary m6A RNA methyltransferase, is significantly upregulated in OSCC cells leading to increased global m6A levels. Interestingly, METTL3 positively regulates miRNAbiogenesis by modulating the processing of primary miRNAs in a m6A-dependent manner. We identified miR-146a-5p, an oncogenic miRNA as one of the METTL3-regulated miRNAs in OSCC. METTL3-depletion or inhibition of its catalytic activity leads to a reduction of miR-146a-5p and an appreciable accumulation of primary miR-146a in OSCC cells. Functional assays examining the effects of miR-146a-5p inhibition or overexpression confirm its oncogenic role in OSCC pathophysiology. Further, SMAD4, a central transducer in TGF-β signaling, was identified as a miR- 146a-5p target. In OSCC cells, SMAD4-depletion exacerbates the oncogenic traits, whereas its overexpression exerts the opposite effect. Additionally, METTL3-depletion dysregulates SMAD4-regulated genes suggesting its potential involvement in SMAD4-dependent TGF-β signaling. Taken together, 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. INTRODUCTION Oral squamous cell carcinoma (OSCC), which develops in the oral mucosa, is one of the most common and aggressive forms of cancer in the head and neck region [1] . OSCC is a growing global health concern, accounting for 389,485 new cases and 188,230 deaths annually, and a five-year mortality rate of 50% that has remained largely unchanged in the past 40 years [2] . The primary treatment for OSCC involves surgical resection followed by chemotherapy and radiotherapy. However, a major challenge in treating OSCC is the difficulty in diagnosing it at an early stage due to the lack of specific signs and symptoms, which often leads to misdiagnosis or advanced-stage detection. Recurrence, tumor invasion, drug resistance, and both local and distant metastases are the leading causes of death in OSCC patients [3] . N6-methyladenosine (m6A) RNA methylation, a well-studied reversible epitranscriptomic modification of RNA, fine-tunes RNA structure and function, thus influencing gene expression by impacting various facets of RNA metabolism such as splicing, stability, nuclear export, and translation, in both normal development and diseased scenarios [4, 5] . Dysregulation of various m6A components i.e., m6A methyltransferases, m

FAQs

What role does METTL3 play in OSCC cells?

METTL3 is significantly upregulated in OSCC and increases global m6A levels, promoting oncogenic behavior and miRNA-related regulatory programs.

How does METTL3 affect miR-146a-5p?

METTL3 positively regulates miR-146a-5p. Depleting METTL3 or inhibiting its catalytic activity reduces miR-146a-5p and leads to accumulation of pri-miR-146a.

What is the relationship between miR-146a-5p and SMAD4 in OSCC?

SMAD4 is identified as a direct miR-146a-5p target. SMAD4 depletion exacerbates oncogenic traits, while SMAD4 overexpression produces the opposite effect.

Sep 24, 2026

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