METTL16 promotes osteosarcoma progression by inducing m6A methylation of the UBE3A and Notch signaling pathway

Abstract

Background: N6-methyladenosine (m⁶A) methylation plays a key role in osteosarcoma (OS) progression. This study aimed to elucidate the function and mechanism of methyltransferase 16 (METTL16), an m⁶A methyltransferase, in OS progression.

Results: Bioinformatics analysis with quantitative reverse-transcription polymerase chain reaction (qRT-PCR) revealed high METTL16 expression in OS. After performing cell functional experiments, METTL16 silencing was shown to decrease the proliferation, migration, and invasion of OS cells. Using qRT-PCR, methylated RNA immunoprecipitation quantitative polymerase chain reaction (MeRIP-qPCR), Western blotting, luciferase, RNA-binding protein immunoprecipitation (RIP), and RNA stability assays, METTL16 induced the m⁶A methylation of ubiquitin protein ligase E3A (UBE3A) to promote UBE3A expression and mRNA stability in OS cells in a fragile X messenger ribonucleoprotein 1 (FMR1)-dependent manner. Moreover, in vitro and in vivo results showed that UBE3A activated the Notch signaling pathway, thereby promoting OS cell malignancy. METTL16 knockdown partly reversed the oncogenic role of UBE3A in OS cells.

Conclusions: METTL16 acts as a tumor promotor in OS progression by modulating UBE3A expression via m⁶A methylation to activate the Notch signaling pathway. The findings highlight the therapeutic potential of disrupting the METTL16–UBE3A–Notch pathway axis in OS.