m6A-Mediated IRS1 Regulates the Development of Oral Squamous Cell Carcinoma through p53/Line-1 Signaling

• Published in: Frontiers in bioscience (Landmark. Print) Vol. 29; no. 7; p. 257
• Main Authors: Xiao, Yanbo, Zhu, Xuan, Li, Qun, Wang, Zongkang, Zuo, Qiaojuan, Liu, Xun, Tan, Jin
• Format: Journal Article
• Language: English
• Published: Singapore IMR Press 19.07.2024
• Subjects: Adenosine - analogs & derivatives; Adenosine - metabolism; Animals; Apoptosis - genetics; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cell Proliferation - genetics; emt; Epithelial-Mesenchymal Transition - genetics; Gene Expression Regulation, Neoplastic; Humans; Insulin Receptor Substrate Proteins - genetics; Insulin Receptor Substrate Proteins - metabolism; irs1; m6a; Mice; Mice, Nude; Mouth Neoplasms - genetics; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; oral squamous cell carcinoma; p53/line-1; Signal Transduction; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; p53/Line-1; m6A; oral squamous cell carcinoma; IRS1; EMT
• ISSN: 2768-6701; 2768-6698; 2768-6698
• DOI: 10.31083/j.fbl2907257

The importance of N6-methyladenosine (m6A) modification in tumorigenesis and progression have been highlighted. This study aimed to investigate the modification of insulin receptor substrate 1 ( ) by m6A and its role in oral squamous cell carcinoma (OSCC). Bioinformatics was employed to predict differential genes related to epithelial-mesenchymal transition (EMT) in OSCC. Seventeen pairs of OSCC and paracancerous tissue samples were collected. The impact of IRS1 on OSCC cell growth and EMT was evaluated. The fluctuations in enrichment and the involvement of p53/Line-1 were investigated. IRS1 was highly expressed in OSCC. IRS1 silencing decreased OSCC cell proliferation and increased apoptosis. IRS1 silencing hindered EMT by regulating related markers. IRS1 silencing upregulated p53 and downregulated Line-1 ORF1p. The p53 inhibition reversed the effects of IRS1 silencing and induced EMT in OSCC cells. Furthermore, the m6A modification of was increased in OSCC cells. IRS1 were positively regulated by the m6A regulators methyltransferase-like 14 (METTL14) and YTH domain-containing protein 1 (YTHDC1). IRS1 bound to YTHDC1, and YTHDC1 knockdown inhibited the IRS1 nuclear export. The obesity-associated protein (FTO) negatively regulated IRS1, and FTO overexpression reversed the IRS1-induced OSCC tumor growth. m6A methylation-mediated regulated EMT in OSCC through p53/Line-1. These findings provide potential therapeutic strategies for managing OSCC.