Upregulated METTL3 in nasopharyngeal carcinoma enhances the motility of cancer cells

Abstract

The roles of RNA m6A modification in carcinogenesis have attracted much interest recently. However, the dysregulation of RNA m6A regulators (writers, readers, and erasers) in nasopharyngeal carcinoma (NPC) has never been reported. In this study, we showed that METTL3, one of the writers, was upregulated in NPC. Functional studies revealed that METTL3 promoted the migration and invasion of NPC cells. However, METTL3 knockdown reversed this effect and inhibited the migration, invasion and metastasis of NPC cells. METTL3 activated the luciferase activity of TOPflash (a reporter for beta‐catenin/TCF signaling), and downregulation of METTL3 inhibited the expression of beta‐catenin/TCF target genes vimentin and N‐cadherin, which are two regulators of epithelial‐mesenchymal transition. Moreover, dominant negative beta‐catenin blocked the migration and invasion of NPC cells. Further mechanistic studies showed that METTL3 silencing decreased the m6A methylation and total mRNA levels of Tankyrase, a negative regulator of axin. Moreover, Tankyrase overexpression abrogated the repressive effects of METTL3 silencing on the migration of NPC cells. Collectively, our study demonstrates the oncogenic roles of METTL3 in NPC, and suggests that METTL3 might be a therapeutic target for NPC.

METTL3‐mediated maturation of miR‐589‐5p promotes the malignant development of liver cancer

“…The most recognized underlying mechanism of m6A modification in cancers is that the methylation process of m6A modification is regulated by methyltransferase 13 . METTL3, as the first reported m6A writer, is a major methyltransferase, and its expression is up‐regulated in different cancers such as gastric cancer, nasopharyngeal carcinoma, cervical cancer and liver cancer 35‐38 . In the current research, highly expressed METTL3 was further confirmed in DLBC, CHOL, THYM and liver cancer, and the level of METTL3 was determined to be negatively correlated with the overall survival.…”

Function of N6-Methyladenosine Modification in Tumors

“…e m6A regulated the metastasis of cancers. METTL3 is upregulated in most tumors, including nasopharyngeal [49], gastric [50], liver [51], and bladder cancers [52], but it is downregulated in colorectal cancer [53].…”

“…The m6A regulated the metastasis of cancers. METTL3 is upregulated in most tumors, including nasopharyngeal [ 49 ], gastric [ 50 ], liver [ 51 ], and bladder cancers [ 52 ], but it is downregulated in colorectal cancer [ 53 ]. The differential expression of METTL3 among tumors plays a dual role, which may reflect differences in targeting pathways and tumor heterogeneity.…”

“…The differential expression of METTL3 among tumors plays a dual role, which may reflect differences in targeting pathways and tumor heterogeneity. Xinyao et al found that knocking out METTL3 downregulated the expression of Snail, thereby reducing the in vitro invasiveness and EMT concentrations in liver cancer cells [ 49 ]. The overexpression of YTHDF2 reduced the expression and stability of mature Snail mRNA in HeLa cells [ 54 ] ( Figure 1(d) ).…”

m6A-dependent upregulation of TRAF6 by METTL3 is associated with metastatic osteosarcoma

“…As we expected, depletion of METTL3 impaired the OS cell abilities to migrate and invade, and most importantly, curbed the EMT process, one important step for cancer cell metastasis. In nasopharyngeal carcinoma cells, downregulation of METTL3 inhibited the expression of EMT markers Vimentin and N-cadherin [21] . Deletion of METTL3 has been previously found to downregulate m6A and to inhibit the migration, invasion and EMT of cancer cells via regulating Snail and JUNB, both major transcription factors of EMT [22] , [23] .…”