The m6A Reader YTHDF3 Promotes Glioma Progression by Regulating the m6A Modification of lncRNA-PAR5.

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Glioma progression is inhibited by long non-coding RNA PAR5 (lncRNA-PAR5), which is downregulated in glioma.
• The precise mechanism behind lncRNA-PAR5 downregulation in glioma remains undetermined.

Purpose of the Study:

• To elucidate the molecular mechanism of PAR5's tumor-suppressive role in glioma.
• To investigate the regulatory role of N6-methyladenosine (m6A) modification in PAR5 expression and function.

Main Methods:

• Bioinformatic prediction of m6A sites in PAR5 and analysis of m6A gene expression in glioblastoma.
• Experimental validation of YTHDF3 binding to PAR5 and its impact on m6A levels using RNA pull-down, RIP-qPCR, and MeRIP-qPCR.
• In vitro and in vivo functional assays to assess the roles of PAR5 and YTHDF3 in glioma cell proliferation, invasion, migration, and tumor growth.

Main Results:

• lncRNA-PAR5 significantly suppressed glioma cell proliferation, invasion, and migration.
• The m6A reader protein YTHDF3 is upregulated in glioma, binds to PAR5, and enhances its m6A modification, leading to PAR5 degradation and suppressed expression.
• YTHDF3 knockdown inhibited glioma progression, while YTHDF3 overexpression promoted it; these effects were partially mediated by PAR5 levels. In vivo studies confirmed YTHDF3 knockdown inhibits tumor growth via PAR5 upregulation.

Conclusions:

• YTHDF3 promotes glioma progression by enhancing m6A modification of PAR5, leading to its degradation.
• The YTHDF3/PAR5 axis is crucial in glioma development, representing a potential therapeutic target.