Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Mol Ther. 2020 Oct 7;28(10):2177-2190. doi: 10.1016/j.ymthe.2020.06.024. Epub 2020 Jun 24.
RNA modification plays an essential function in regulating gene expression and diverse biological processes. RNA modification enzyme methyltransferase-like 3 (METTL3) affects tumor progression by regulating the N-methyladenosine (mA) modification in the mRNAs of critical oncogenes or tumor suppressors, but its effect in oral squamous cell carcinoma (OSCC) remains unknown. In this study, we revealed that METTL3 was consistently upregulated in two OSCC cohorts, and high METTL3 expression was associated with poor prognosis. Functionally, cell proliferation, self-renewal, migration, and invasion ability in vitro and tumor growth and metastasis in vivo were decreased after METTL3 knockdown in OSCC cells. In contrast, the opposite results were obtained after METTL3 overexpression. In addition, the results obtained with the Mettl3 genetically modified mouse model validated the essential role of Mettl3 in chemical-induced oral carcinogenesis. In mechanism, methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP-quantitative real-time PCR, and luciferase reporter and mutagenesis assays identified that METTL3 mediates the mA modification in the 3' UTR of BMI1 mRNA. METTL3 promotes BMI1 translation in OSCC under the cooperation with mA reader IGF2BP1. Our findings revealed that METTL3 promotes OSCC proliferation and metastasis through BMI1 mA methylation, suggesting that the METTL3-mA-BMI1 axis may serve as a prognostic biomarker or therapeutic target in patients with OSCC.
RNA 修饰在调节基因表达和多种生物过程中起着至关重要的作用。RNA 修饰酶甲基转移酶样 3（METTL3）通过调节关键癌基因或肿瘤抑制因子 mRNA 中的 N6-甲基腺苷（m6A）修饰来影响肿瘤进展，但它在口腔鳞状细胞癌（OSCC）中的作用尚不清楚。在这项研究中，我们揭示了 METTL3 在两个 OSCC 队列中持续上调，并且高 METTL3 表达与预后不良相关。功能上，METTL3 敲低后，OSCC 细胞的体外增殖、自我更新、迁移和侵袭能力以及体内肿瘤生长和转移能力降低；相反，METTL3 过表达后则获得相反的结果。此外，利用 Mettl3 基因修饰小鼠模型获得的结果验证了 Mettl3 在化学诱导的口腔致癌作用中的重要作用。在机制上，甲基化 RNA 免疫沉淀测序（MeRIP-seq）、MeRIP-qPCR 和荧光素酶报告基因和突变检测鉴定了 METTL3 介导了 BMI1 mRNA 3'UTR 中的 m6A 修饰。METTL3 在与 m6A 阅读器 IGF2BP1 的合作下，促进 OSCC 中的 BMI1 翻译。我们的研究结果表明，METTL3 通过 BMI1 m6A 甲基化促进 OSCC 的增殖和转移，提示 METTL3-m6A-BMI1 轴可能作为 OSCC 患者的预后生物标志物或治疗靶点。
