METTL3 介导的 ALDH mA 甲基化调节 BMI1 HNSCC 干细胞的恶性行为。
METTL3-mediated ALDH mA methylation regulates the malignant behavior of BMI1 HNSCC stem cells.
机构信息
Department of Oral and Maxillofacial Surgery, Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China.
出版信息
Oral Dis. 2024 Apr;30(3):1061-1071. doi: 10.1111/odi.14609. Epub 2023 May 30.
OBJECTIVES
To reveal the effect and mechanism of methyltransferase-like 3 (METTL3) on cancer stem cells (CSCs) of head and neck squamous cell carcinoma (HNSCC).
MATERIALS AND METHODS
First, we analyzed 14-HNSCC-patients' scRNA-seq dataset and TCGA dataset of HNSCC. Then, Mettl3 knockout or overexpression mice models were studied via tracing and staining technologies. In addition, we took flow cytometry sorting and sphere formation assays to observe tumorigenicity and used cell transfection and western blotting to verify target protein expression levels. Furthermore, methylated RNA immunoprecipitation sequencing (MeRIP-seq) and MeRIP-quantitative real-time PCR (MeRIP-qPCR) were taken to identify the mechanism of Mettl3 regulating Bmi1 CSCs in HNSCC.
RESULTS
Due to SOX4 transcriptional regulation, METTL3 regulated the malignant behavior of BMI1 HNSCC stem cells through cell division pathway. The progression and malignancy of HNSCC were decreased after Mettl3 knocked-out, while increased after Mettl3 knocked-in in Bmi1 CSCs in vivo. Knockdown of Mettl3 inhibited stemness properties of CSCs in vitro. Mechanically, Mettl3 mediated the mA modification of ALDH1A3 and ALDH7A1 mRNA in Bmi1 HNSCC CSCs.
CONCLUSION
Regulated by SOX4, METTL3-mediated ALDH mA methylation regulates the malignant behavior of BMI1 HNSCC CSCs through cell division pathway.
目的
揭示甲基转移酶样 3（METTL3）对头颈鳞状细胞癌（HNSCC）癌症干细胞（CSC）的作用和机制。
材料和方法
首先，我们分析了 14 例 HNSCC 患者的 scRNA-seq 数据集和 HNSCC 的 TCGA 数据集。然后，通过示踪和染色技术研究了 Mettl3 敲除或过表达的小鼠模型。此外，我们采用流式细胞术分选和球体形成实验观察肿瘤发生能力，并通过细胞转染和 Western blot 验证靶蛋白表达水平。此外，采用甲基化 RNA 免疫沉淀测序（MeRIP-seq）和 MeRIP 定量实时 PCR（MeRIP-qPCR）来确定 Mettl3 调节 HNSCC 中 Bmi1 CSCs 的机制。
结果
由于 SOX4 的转录调控，METTL3 通过细胞分裂途径调节 BMI1 HNSCC 干细胞的恶性行为。在体内敲除 Mettl3 后，Bmi1 CSCs 的进展和恶性程度降低，而敲入 Mettl3 后则增加。体外敲低 Mettl3 抑制了 CSCs 的干性特征。在机制上，Mettl3 介导了 Bmi1 HNSCC CSCs 中 ALDH1A3 和 ALDH7A1 mRNA 的 mA 修饰。
结论
受 SOX4 调控，METTL3 介导的 ALDH mA 甲基化通过细胞分裂途径调节 BMI1 HNSCC CSCs 的恶性行为。
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