Jayaprakash Jayasree Peroth, Karemore Pragati, Khandelia Piyush
Laboratory of Molecular Medicine, Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Hyderabad 500078, India.
Oncotarget. 2025 May 8;16:291-309. doi: 10.18632/oncotarget.28717.
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 miRNA biogenesis 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.
N6-甲基腺苷（m6A）是真核生物RNA中最显著且可逆的内部修饰之一，已成为包括口腔鳞状细胞癌（OSCC）在内的多种癌症中基因表达的关键调节因子，在其中它塑造了肿瘤特异性的表观转录组基因调控网络。METTL3是主要的m6A RNA甲基转移酶，在OSCC细胞中显著上调，导致整体m6A水平升高。有趣的是，METTL3通过以m6A依赖的方式调节初级miRNA的加工来正向调节miRNA的生物发生。我们鉴定出miR-146a-5p，一种致癌性miRNA，是OSCC中METTL3调节的miRNA之一。METTL3的缺失或其催化活性的抑制导致OSCC细胞中miR-146a-5p减少以及初级miR-146a明显积累。检测miR-146a-5p抑制或过表达影响的功能试验证实了其在OSCC病理生理中的致癌作用。此外，SMAD4是TGF-β信号传导中的核心转导子，被鉴定为miR-146a-5p的靶标。在OSCC细胞中，SMAD4的缺失会加剧致癌特性，而其过表达则产生相反的效果。此外，METTL3的缺失会使SMAD4调节的基因失调，表明其可能参与SMAD4依赖的TGF-β信号传导。综上所述，我们报道METTL3作为一种癌基因通过miR-146a-5p调节肿瘤抑制因子SMAD4的表达，从而揭示了OSCC中METTL3/miR-146a-5p/SMAD4的新型调控轴，这可能具有潜在的治疗意义。
