Loss of NSUN6 inhibits osteosarcoma progression by downregulating EEF1A2 expression and activation of Akt/mTOR signaling pathway via m5C methylation.

Abstract

As an important 5-methylcytidine (m5C) methyltransferase, NOP2/Sun RNA methyltransferase family member 6 (NSUN6) has been reported to play an important role in the progression of several diseases. However, the role of NSUN6 in the progression of osteosarcoma (OS) remains unclear. This study aimed to identify the role of NSUN6 in the progression of OS and clarify the potential molecular mechanism. The present study discovered that NSUN6 was upregulated in OS and a higher NSUN6 expression was a strong indicator for poorer prognosis of patients with OS. In addition, the loss of NSUN6 led to reduced proliferation, migration and invasion of OS cells. Through bioinformatics analysis, RNA immunoprecipitation (RIP) and methylated RIP assays, eukaryotic elongation factor 1 α-2 (EEF1A2) was identified and validated as a potential target of NSUN6 in OS. Mechanistically, the expression of EEF1A2 was significantly suppressed following NSUN6 knockdown due to reduced EEF1A2 mRNA stability in an m5C-dependent manner. Meanwhile, NSUN6 deficiency inhibited m5C-dependent activation of Akt/mTOR signaling pathway. In addition, genetic overexpression of EEF1A2 or pharmacological activation of the Akt signaling pathway counteracted the suppressive effects of NSUN6 deficiency on the proliferation, invasion and migration of OS cells. The current findings suggested that NSUN6 may serve as a potential therapeutic target for OS treatment.