N6-Methyladenosine Methyltransferase METTL14-Mediated Autophagy in Malignant Development of Oral Squamous Cell Carcinoma

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.

Functions, mechanisms, and therapeutic implications of METTL14 in human cancer

“…METTL14 was downregulated and correlated with lymph node metastasis of CRPC and was negatively correlated with the Gleason grade in PCa [ 130 ]. METTL14 was downregulated in triple-negative breast cancer (TNBC) [ 118 ], esophageal cancer (EC) [ 131 ], gastric cancer [ 132 ], osteosarcoma (OS) [ 133 ],Wilms tumor, [ 134 ] and oral squamous cell carcinoma (OSCC) [ 135 ], and low METTL14 expression was related to poor prognosis. Notably, it has been confirmed that METTL14 knockout can activate Wnt and PI3K-Akt signals to promote the growth and invasion of gastric cancer cells [ 132 ].…”

Translational Regulation by eIFs and RNA Modifications in Cancer

“…The formation of complexes reduces the chemosensitivity of bladder cancer to chemotherapeutic agents [ 261 ]. METTL14 directly binds to eIF4G1 mRNA and reduces the stability of eIF4G1 RNA by mediating m 6 A modification, thereby regulating autophagy levels and effectively reducing the growth of oral squamous cell carcinoma [ 262 ]. METTL16 is an RNA methyltransferase primarily responsible for the deposition of N6-methyladenosine (m 6 A) in transcripts.…”

Roles of m6A modification in oral cancer (Review)

“…m 6 A methyltransferase is involved in the development of cancers. Several studies have indicated that METTL3 and METTL14 are closely associated with cancer cell proliferation, the epithelial to mesenchymal transition (EMT) process and autophagy, and are essential genes to regulate intracellular activities (38)(39)(40)(41)(42)(43).…”

“…YTHDF2 is related to autophagy and metastasis, IGF2BP1 is involved in the metastasis process of cancer cells and IGF2BP2 has a vital role in autophagy and proliferation. HNRNPC and HNRNPA2B1 promotes the EMT process (20,39,41,(54)(55)(56)(57).…”

“…Therefore, reducing the m 6 A level of eIF4G1 may upregulate the expression of eIF4G1, inhibit autophagy and promote the migration, invasion and proliferation of oral cancer cells ( 59 ). In addition, the METTL14 level in cancer tissues of patients with advanced oral tumors was low and the autophagy level decreased after METTL14 was silenced within oral cancer cells ( 39 ). Further exploration revealed that METTL14 downregulated the stability of eIF4G1mRNA using YTHDF2-mediated m 6 A to promote autophagy and inhibit oral cancer development ( 39 ).…”