In a groundbreaking study published in the latest volume of Oncotarget, researchers from the Birla Institute of Technology and Science, India, unveiled a novel molecular axis that drives oral squamous cell carcinoma (OSCC), a highly aggressive form of cancer affecting the mouth and throat. This newly discovered pathway centers on METTL3, an RNA methyltransferase enzyme, which modulates RNA methylation and profoundly influences gene regulation within cancer cells. The study elucidates how METTL3 exacerbates OSCC progression by manipulating the miR-146a-5p/SMAD4 axis, offering promising avenues for targeted therapies against this lethal disease.
Oral squamous cell carcinoma remains a significant clinical challenge, with late diagnosis and rapid metastasis contributing to its high mortality rate worldwide. The research team focused on METTL3, a primary m6A RNA methyltransferase responsible for installing N6-methyladenosine marks on RNA transcripts. These epigenetic modifications are well documented to impact RNA stability, splicing, translation efficiency, and degradation, thereby controlling gene expression post-transcriptionally. Intriguingly, elevated METTL3 activity has been reported across various cancers, yet its precise role in OSCC was hitherto unclear.
The study reveals that in OSCC cells, METTL3 is markedly upregulated, leading to globally increased m6A methylation levels. This epitranscriptomic surge promotes the enhanced processing of the primary microRNA precursor pri-miR-146a into its mature form, miR-146a-5p. miRNAs like miR-146a-5p play pivotal roles in gene silencing by binding to complementary sequences in target messenger RNAs (mRNAs), resulting in their degradation or translational repression. Here, the mature miR-146a-5p directly targets SMAD4, a well-known tumor suppressor gene critical for cellular growth regulation and apoptotic pathways.
SMAD4 functions as a central mediator within the transforming growth factor-beta (TGF-β) signaling cascade, which coordinates cellular proliferation, differentiation, and programmed cell death—processes frequently dysregulated in cancers. The downregulation of SMAD4 by miR-146a-5p, as orchestrated by METTL3-mediated m6A modifications, dismantles this tumor-suppressing pathway. Consequently, OSCC cells exhibit increased proliferation, enhanced colony formation, greater migratory and invasive capacities, alongside reduced apoptosis. This comprehensive disruption not only facilitates tumor growth but also contributes to metastasis and treatment resistance observed clinically.
Experimental manipulations further substantiated this molecular interplay. Silencing METTL3 or pharmacologically inhibiting its methyltransferase activity led to a significant decrease in miR-146a-5p levels while restoring SMAD4 expression in OSCC cell lines. These changes culminated in attenuated malignant behaviors, including slower cell division rates and heightened sensitivity to apoptotic stimuli. Conversely, reintroducing miR-146a-5p or knocking down SMAD4 reversed these effects, confirming the essential role of the METTL3-miR-146a-5p-SMAD4 axis in disease progression.
These insights carry profound therapeutic implications. Targeting this newly identified molecular cascade might revolutionize OSCC management by curbing the cancer’s aggressive features. Notably, STM2457, a small-molecule inhibitor of METTL3 previously investigated in other malignancies such as acute myeloid leukemia, exhibited promising anti-tumor activity in vitro by impairing METTL3 function. Leveraging METTL3 inhibitors, alongside strategies to block miR-146a-5p or restore SMAD4, could potentially suppress OSCC growth and dissemination more effectively than existing treatments.
Moreover, the elucidation of this epigenetic regulatory mechanism enriches our understanding of RNA modifications in cancer biology. The m6A RNA methylation landscape, shaped by enzymes like METTL3, has emerged as a crucial layer of gene control that cancer cells exploit for survival and expansion. This study highlights the need to explore RNA methylomics further, underscoring how intricate post-transcriptional modifications can drive tumorigenesis through microRNA-mediated pathways.
The discovery also sheds light on why OSCC remains recalcitrant to conventional therapies. By illuminating a cancer-promoting axis that suppresses intrinsic tumor-suppressive machinery, this research suggests that future therapeutic development should integrate epigenetic and RNA-based approaches in addition to traditional chemotherapy and radiation. Such integrated efforts could improve patient outcomes by sensitizing tumors to therapy and preventing relapse.
From a clinical diagnostics perspective, the elevated expression of METTL3 and miR-146a-5p alongside reduced SMAD4 may serve as valuable biomarkers for OSCC prognosis, detection, and treatment stratification. Non-invasive assays to monitor these molecules could enhance early diagnosis when interventions are most effective, thereby reducing OSCC-related mortality.
In summary, the investigation by Jayaprakash, Karemore, and Khandelia introduces the METTL3/miR-146a-5p/SMAD4 axis as a critical regulatory pathway underpinning OSCC progression. Through the aberrant upregulation of RNA methylation and subsequent microRNA dysregulation, this axis disrupts tumor-suppressive controls to favor aggressive cancer phenotypes. Targeting components of this axis holds significant promise for developing innovative and precise treatments for a disease that continues to impose a substantial global health burden.
As RNA epigenetics gains momentum in cancer research, this study exemplifies the therapeutic potential of modulating RNA modifiers like METTL3. The interplay between epitranscriptomic modifications, microRNAs, and tumor suppressors expands the landscape of actionable molecular targets. Continued exploration in this realm is poised to transform how clinicians understand, diagnose, and treat oral squamous cell carcinoma, heralding a new era in cancer therapeutics grounded in RNA biology.
Subject of Research: Cells
Article Title: METTL3 promotes oral squamous cell carcinoma by regulating miR-146a-5p/SMAD4 axis
News Publication Date: 8-May-2025
Web References:
http://dx.doi.org/10.18632/oncotarget.28717
Image Credits:
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).
Keywords: cancer, oral cancer, m6A RNA methylation, METTL3, miR-146a-5p, SMAD4
