METTL3 stabilizes HDAC5 mRNA in an m⁶A-dependent manner to facilitate malignant proliferation of osteosarcoma cells

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Osteosarcoma (OS) is a primary bone cancer with significant morbidity.
• Dysregulation of methyltransferase-like 3 (METTL3) is implicated in various cancers.
• The precise role of METTL3 in OS pathogenesis requires further elucidation.

Purpose of the Study:

• To investigate the mechanism by which METTL3 influences osteosarcoma cell proliferation.
• To identify key molecular players in the METTL3-mediated signaling pathway in OS.

Main Methods:

• Analysis of METTL3 expression in OS patient samples and correlation with clinical parameters.
• In vitro studies involving METTL3 silencing and overexpression in OS cell lines.
• Investigation of the m6A modification, histone deacetylase 5 (HDAC5), miR-142-5p, and armadillo-repeat-containing 8 (ARMC8) interactions.
• In vivo xenograft tumor experiments in nude mice.

Main Results:

• METTL3 was highly expressed in OS, correlating with tumor size, stage, metastasis, and poorer prognosis.
• METTL3 silencing inhibited OS cell proliferation, while overexpression promoted it.
• METTL3 upregulated HDAC5 via m6A modification, leading to decreased miR-142-5p and increased ARMC8.
• The HDAC5/miR-142-5p/ARMC8 axis mediated the effect of METTL3 on OS proliferation in vitro and in vivo.

Conclusions:

• METTL3 promotes osteosarcoma cell proliferation through the HDAC5/miR-142-5p/ARMC8 pathway.
• METTL3-mediated m6A modification is a critical driver of OS progression.
• Targeting METTL3 may represent a therapeutic strategy for osteosarcoma.