METTL3 Intensifies the Progress of Oral Squamous Cell Carcinoma via Modulating the m6A Amount of PRMT5 and PD-L1

Abstract

N6-Methyladenosine (m6A) modification is one of the commonest chemical modifications in eukaryotic mRNAs, which has essential effects on mRNA translation, splicing, and stability. Currently, there is a rising concern on the regulatory role of m6A in tumorigenesis. As a known component in the m6A methyltransferase complex, METTL3 (methyltransferase-like 3) plays an essential role in m6A methylation. Till now, the functions of METTL3 in oral squamous cell carcinoma (OSCC) and its relative mechanism remain to be explored. In this research, through the GEPIA database, we found that high METTL3 expression has a correlation with poor prognosis of squamous cell carcinoma of head and neck. qRT-PCR displayed that METTL3 was highly expressed in OSCC cells. Functionally, METTL3 knockdown reduced the invasion, migration, and proliferation competence of OSCC cells and attenuated the activation of CD8+ T cells. In contrast, METTL3 overexpression resulted in opposite results. GEPIA, UALCAN, and SRAMP databases, PCR, western blot, and m6A RNA methylation assay confirmed the m6A modification of PRMT5 and PD-L1 mediated by METTL3. In conclusion, our results displayed that METTL3 intensified the metastasis and proliferation of OSCC by modulating the m6A amounts of PRMT5 and PD-L1, suggesting that METTL3 may be a therapeutic target for OSCC patients.

METTL3 is a Potential Prognostic Biomarker in Head and Neck Squamous Cell Carcinoma

“…Studies have shown that the risk score composed of the m 6 A gene is related to the in ltration of dendritic cells, neutrophils, CD4 + T cells, CD8 + T cells, and B cells, and upregulated m 6 A regulators are positively correlated with PD-L1 in the HNSCC tumor immune microenvironment [38]. Ai Y et al found that highly expressed METTL3 promotes the progression of oral squamous cell carcinoma by inhibiting the activation of CD8 + T cells and modulating the m 6 A levels of PRMT5 and PD-L1 [39]. Other researchers have found that METTL3 is upregulated and associated with poor prognosis in oral squamous cell carcinoma [40], which was consistent with our study although the difference was not signi cant (Fig.…”

Role of m6A writers, erasers and readers in cancer

“…METTL3 regulates the m6A levels on EZH2, tankyrase and snail and promotes the progression of nasopharyngeal carcinoma [296][297][298]. METTL3 may regulate the expression of PRMT5, PD-L1 and c-MYC through m6A to promote the progression of oral squamous cell carcinoma [299,300]. YTHDC2 physically binds to insulin-like growth factor 1 receptor (IGF1R) mRNA to promote the translation of IGF1R mRNA, which in turn activates the IGF1-AKT/S6 signaling pathway and promotes radiotherapy resistance in nasopharyngeal carcinoma cells [301].…”

Current insight into the regulation of PD-L1 in cancer

“…METTL3 mediates the RNA methylation modification process and functionally catalyzes m6A mRNA methylation [ 89 ]. By increasing the m6A content in protein arginine methyltransferase 5 (PRMT5) and PD-L1, METTL3 promotes the metastasis and proliferation of OSCC [ 90 ]. Through a m6A-dependent mechanism, METTL3 positively regulates IGF2BP3 to increase the stability and expression of PD-L1 mRNA in BC [ 91 ].…”

“…MLL1 ↑PC [134] NRF2 ↑HCC [22] ATF3 ↑melanoma and NSCLC [55] Epigenetic regulation of PD-L1 DNA methylation ↓melanoma [62,64], leukemia [39] Histone modification ↓BC and B cell lymphomas [53,185], lung cancer [66] MicroRNAs shown in Table 1 N6-methyladenosine ↑OSCC [90], ↑BC [91] LncRNA and circRNA HOTTIP, SNHG12, EMX2OS-↑OC[76, 77, 81] SNHG20-↑esophagus cancer [78] CASC11-↑HCC [80] SNHG14-↑DLBCL [79] NUTM2A-AS1-↑GC [82] Hoxa-AS2-↑nasopharyngeal carcinoma [83] IFITM4P-↑OSCC [84] LncMX1-215-↓HNSCC [85] Hsa_circ_0000190-↑NSCLC [186] HasCircRNA-002178-↑ LUAD [87] CDR1-AS-↑CC [88] PD-L1 regulation at the protein level Ubiquitination ↓ BC [97], NSCLC [98], CC [99], colon cancer [100], melanoma [101,102,106], lung cancer [101], esophageal squamous cell carcinoma [105] Glycosylation ↑AML [108], TNBC [109,111], colon cancer [110], prostate cancer [111], glioma [112] Phosphorylation ↓ BC [114,116], HCC [115] Acetylation ↓ multiple cancers [117] Palmitoylation ↑ BC and colon cancer [118,…”