CKS2, regulated by METTL3, contributes to osteosarcoma progression in an IGF2BP1-dependent manner

Area of Science:

• Molecular Biology
• Oncology
• Epigenetics

Background:

• Osteosarcoma (OS) pathogenesis involves N6-methyladenosine (m⁶A) RNA modification.
• Downstream effectors and regulatory networks of m⁶A in OS are not fully understood.
• Cyclin-dependent kinase subunit 2 (CKS2) is a potential key player in OS progression.

Purpose of the Study:

• To investigate the role of CKS2 in osteosarcoma progression.
• To elucidate the regulation of CKS2 by METTL3-mediated m⁶A modification.
• To identify the regulatory network involving CKS2, METTL3, and IGF2BP1 in OS.

Main Methods:

• Analysis of differentially expressed genes (DEGs) from the GEO database (GSE16088).
• Validation of candidate targets in OS tissues using qRT-PCR.
• In vitro and in vivo assays to examine CKS2 function.
• Bioinformatics, correlation analysis, RIP, MeRIP, Western blotting, and mRNA stability assays to analyze molecular relationships.
• Rescue experiments to explore functional interactions.

Main Results:

• CKS2 was significantly upregulated in OS tissues and its silencing inhibited OS cell proliferation, migration, invasion, and tumor growth.
• METTL3 expression positively correlated with CKS2 levels, and METTL3 overexpression enhanced CKS2 mRNA stability in an m⁶A-dependent manner.
• IGF2BP1 directly bound to m⁶A-modified CKS2 transcripts, maintaining their stability. METTL3 overexpression partially rescued CKS2 silencing effects.

Conclusions:

• A novel METTL3/IGF2BP1-CKS2 axis promotes osteosarcoma progression.
• This axis functions through m⁶A-dependent mRNA stabilization of CKS2.
• CKS2 represents a potential therapeutic target for osteosarcoma treatment.