The m6A methyltransferase METTL3 promotes osteosarcoma progression by regulating the m6A level of LEF1

Abstract

Osteosarcoma(OS) is the most common and aggressive malignant bone sarcoma,which occurs in rapidly growing bones in children and adolescents. However, the underlying molecular mechanisms of OS development have not been fully illustrated. N6-Methyladenosine (m6A) is the most prevalent internal chemical modification of mRNAs, which is involved in many pathological processes in cancer development. However, its role and regulatory mechanism in OS remain unknown. In this study, we aimed to investigate the roles of m6A and its methyltransferase METTL3 in OS development. The results showed that m6A level for RNA methylation and the expression level of METTL3 were up-regulated in human OS tissues and OS cell lines. Functionally, lentivirus-mediated METTL3 silence in HOS and SAOS-2 cells inhibited the cell proliferation, migration and invasion ability. Further mechanism analysis suggested that METTL3 silence decreased the m6A methylation and total mRNA level of lymphoid enhancer-binding factor 1 (LEF1), followed by inhibited the activity of Wnt/β-catenin signaling pathway. Moreover, LEF1 over-expression abrogates the repressive effects of METTL3 silence on the proliferation, migration and invasion abilities of OS cells. Together, these results revealed that the m6A methyltransferase METTL3 promotes osteosarcoma cell progression by regulating the m6A level of LEF1 and activating Wnt/β-catenin signaling pathway.

Keywords: LEF1; METTL3; Osteosarcoma; m6A.