METTL3-mediated ALDH m6 A methylation regulates the malignant behavior of BMI1+ HNSCC stem cells

Zhi Chen; Jie Chen; Xiaohong Xu; Qiuli Li; Caihua Zhang; Shuai Li; Lianlian Liu; Congyuan Cao; Demeng Chen; Qianting He

doi:10.1111/odi.14609

METTL3-mediated ALDH m⁶ A methylation regulates the malignant behavior of BMI1⁺ HNSCC stem cells

Oral Dis. 2023 May 30. doi: 10.1111/odi.14609. Online ahead of print.

Authors

Zhi Chen¹, Jie Chen², Xiaohong Xu³, Qiuli Li⁴, Caihua Zhang¹, Shuai Li¹, Lianlian Liu¹, Congyuan Cao¹, Demeng Chen¹, Qianting He¹

Affiliations

¹ Department of Oral and Maxillofacial Surgery, Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
² Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China.
³ Department of Stomatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁴ 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, China.

PMID: 37249063
DOI: 10.1111/odi.14609

Abstract

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 m⁶ A modification of ALDH1A3 and ALDH7A1 mRNA in Bmi1⁺ HNSCC CSCs.

Conclusion: Regulated by SOX4, METTL3-mediated ALDH m⁶ A methylation regulates the malignant behavior of BMI1⁺ HNSCC CSCs through cell division pathway.

Keywords: ALDH; BMI1; CSCs; HNSCC; METTL3; SOX4.

Abstract

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