Abstract
N6-methyladenosine (m6A) is the most abundant internal mRNA modification in eukaryotes and is related to stability, localization, or translation efficiency in tumorigenesis. Autophagy plays an important role in the occurrence and development of tumours. However, the relationship between m6A and autophagy remains unclear. In this study, we used a rapamycin-induced autophagy model of oral squamous cell carcinoma (OSCC) cells, and observed increased m6A RNA methylation. When autophagy was activated, the methyltransferase-like 14 (METTL14) expression was upregulated and influenced the proliferation, migration, and invasiveness of OSCC cells. Through meRIP-seq and RNA-seq analysis, we found that METTL14 directly combined with eukaryotic translation initiation factor gamma 1 (eIF4G1) mRNA and decreased its RNA stability. According to the dual-luciferase reporter and mutagenesis assay, the mutated site 1 of exon 11 of eIF4G1 is the key target of METTL14. Knockdown of the main m6A binding protein YTHDF2 may rescue the shortened half-life of eIF4G1 mRNA induced by METTL14 overexpression. Furthermore, an in vivo tumour xenograft model confirmed that a high METTL14 expression can effectively reduce OSCC growth. Additionally, using clinical samples, we found that patients with advanced or moderately/poorly differentiated tumours exhibited lower METTL14 levels. Taken together, our results revealed that METTL14 mediated eIF4G1 expression via m6A modification and regulated autophagy levels and biological functions in OSCC. Our findings not only expand our understanding of the correlation between autophagy and RNA methylation in tumorigenesis but also present an opportunity to develop new therapeutic options.
Highlights
Oral cancer is one of the most common malignant tumours in the head and neck region
We found that the methylation level of N6 methyladenine (m6A) increased in a rapamycin-induced autophagy cell model of oral squamous cell carcinoma (OSCC), indicating that m6A RNA methylation may be involved in the activation of autophagy in OSCC cells. m6A RNA is a methylated nucleoside occurring at the sixth nitrogen atom of adenine and is the most abundant form of eukaryotic mRNA expression [16]
When autophagy was induced by rapamycin or inhibited by 3MA in vitro, we found that m6A modification was upregulated or downregulated, respectively, in OSCC cells (Figure 1A), suggesting that m6A methylation may be involved in autophagy activation in OSCC cells
Summary
Oral cancer is one of the most common malignant tumours in the head and neck region. Oral squamous cell carcinoma (OSCC) is the most common subtype of oral cancer, accounting for approximately 90% of cases [1, 2]. This type of carcinoma is highly invasive, often infiltrating and developing rapidly. Despite the rapid development and progress in imaging, surgery, radiotherapy, and multidisciplinary treatments, the five-year overall survival rate of patients with OSCC is approximately 50%, which is significantly lower than that of patients with other tumours [5, 6]. It is of great clinical significance to study the invasion and metastasis molecular mechanisms of OSCC, which could aid in the development of new methods for early diagnosis and treatment
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