METTL3-mediated m6A methylation of lncRNA PVT1 promotes the progression of oral squamous cell carcinoma via the miR-185-5p/SERPINB4 axis

Abstract

Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors of the head and neck region. Plasmacytoma variant translocation 1 (PVT1), a long non-coding RNA (lncRNA), has been found to be overexpressed in multiple cancers, including OSCC. However, the upstream and downstream regulatory mechanisms through which PVT1 influences the malignant progression of OSCC remain to be further explored. In this study, PVT1 was confirmed to be overexpressed in OSCC tissues, and its roles in promoting OSCC cell proliferation, migration and invasion were identified. RNA-sequencing was used to screen the candidate target genes of PVT1, among which serpin family B member 4 (SERPINB4) was the most downregulated. SERPINB4 promoted OSCC cell proliferation, migration and invasion. In addition, mechanistic investigations demonstrated that PVT1 regulates SERPINB4 by sponging miR-185-5p in OSCC cells. Furthermore, SERPINB4 overexpression or miR-185-5p knockdown partly restores the decrease of OSCC cell proliferation and metastasis induced by PVT1 knockdown. Additional studies revealed that methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m⁶A) modification induced the upregulation of PVT1 by stabilizing its RNA transcript. In conclusion, elevated expression of PVT1 in OSCC is associated with poor prognosis and promotes tumor development. METTL3 promotes PVT1 stability through m⁶A deposition and upregulates its expression in OSCC, which could upregulate SERPINB4 by sponging miR-185-5p, and ultimately promoting OSCC growth and metastasis. These findings suggest that PVT1 could serve as a potential biomarker and therapeutic target for OSCC.