METTL3-induced UCK2 m6A hypermethylation promotes melanoma cancer cell metastasis via the WNT/β-catenin pathway

Abstract

Background: Melanoma is a highly aggressive, malignant skin tumor with a statistically high mortality rate. N6-methyladenosine (m 6 A) modification is involved in a variety of biological processes, including tumorigenesis. m 6 A modifications regulate the fate and functions of RNA, such as mRNA stability, nuclear processing, transport, localization, translation, primary microRNA (miRNA) processing, and RNA-protein interactions. Several members (including METTL3, METTL14, FTO, ALKBH5, and YTHDF2) are actively involved in a variety of human cancers. However, the basic mechanism of the involvement of uridine cytidine kinase 2 (UCK2) in melanoma metastasis has not been studied. UCK2 is upregulated in a variety of malignancies. However, the complex molecular mechanisms and therapeutic effects of UCK2 in melanoma remain unclear.Methods: The expression of UCK2 was evaluated by qRT-PCR. The effects of UCK2 on the biological characteristics of PC cells were investigated on the basis of loss-of-function analyses. Immunoprecipitation-qPCR (MeRIP-qPCR) was performed to identify the m 6 A targeted effect of UCK2 in melanoma cancer.Results: Based on the bioinformatics analysis in this study, up-regulation of UCK2 could be essential in melanoma cancer, and associated with poor survival. Furthermore, the m 6 A modification regulated by METTL3 led to UCK2 increased messenger RNA (mRNA) stability in melanoma cancer. Functional and mechanistic experiments indicated that UCK2 enhanced the metastasis of melanoma cancer cells through the WNT/β-catenin pathway. Conclusion:In this study, we found that m 6 A-METTL3 axis induced abnormal UCK2 expression plays a role in melanoma metastasis by enhancing the Wnt/β-catenin pathway, which may provide new clues for melanoma metastasis. It also provides a potential target for the prevention and treatment of melanoma.

METTL3‐m6A methylase regulates the osteogenic potential of bone marrow mesenchymal stem cells in osteoporotic rats via the Wnt signalling pathway

“…Similarly, Dickkopf‐1 (DKK1) can reduce the osteogenic potential of BMSCs and cause bone loss 31,32 . Previous studies have shown that Mettl3 could regulate the Wnt/β‐catenin pathway 33,34 . However, the regulatory mechanism of Mettl3 influences the bone differentiation of OP‐BMSCs through the canonical Wnt pathway is unknown.…”

m6A Methyltransferase METTL3 Promotes the Progression of Primary Acral Melanoma via Mediating TXNDC5 Methylation

“…Wu et al. found that UCK2 overexpression was regulated by m 6 A-METTL3 axis in melanoma metastasis ( 53 ); Chang et al. proposed that miR-302a-3p targets and suppresses the expression of METTL3 to inhibit melanoma cell progression ( 54 ).…”

Role of m6A writers, erasers and readers in cancer

“…The role played by m6A in melanoma is not fully understood, and only a few research results have been reported. A study found that METTL3 induced UCK2 m6A hypermethylation and promoted the metastasis of melanoma cells through the WNT/β-catenin pathway [ 290 ]. METTL3 may be involved in the proliferation, invasion, migration and resistance of melanoma cells [ 291 , 292 ].…”