The m6A Reader YTHDF2 Promotes Bladder Cancer Progression by Suppressing RIG-I-Mediated Immune Response

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• N6-Methyladenosine (m6A) is a key mRNA modification in mammals.
• METTL3 and METTL14 are implicated in urothelial bladder carcinoma (BLCA).
• The role of m6A readers, like YTHDF2, in BLCA requires further investigation.

Purpose of the Study:

• To investigate the role of YTHDF2, an m6A reader, in BLCA.
• To elucidate the downstream targets and mechanisms of YTHDF2 in BLCA.
• To assess the therapeutic potential of targeting YTHDF2 in BLCA.

Main Methods:

• Analysis of YTHDF2 expression in BLCA tissues.
• In vitro and in vivo functional assays (proliferation, tumor growth).
• Integrative RNA sequencing and m6A sequencing.
• Western blotting and RT-qPCR for gene expression analysis.
• Orthotopic implantation models and immunotherapy studies.

Main Results:

• YTHDF2 is upregulated in BLCA at both RNA and protein levels.
• YTHDF2 promotes BLCA cell proliferation and tumor growth.
• YTHDF2 targets RIG-I (encoded by DDX58) for degradation via m6A-dependent mechanisms.
• RIG-I knockdown mimics YTHDF2's pro-tumorigenic effects.
• YTHDF2 deficiency enhances anti-tumor immunity (CD8+ T cell recruitment) and immunotherapy efficacy.

Conclusions:

• YTHDF2 functions as an oncogene in BLCA by inhibiting RIG-I and promoting immune evasion.
• Targeting YTHDF2 may represent a novel therapeutic strategy for BLCA, particularly in combination with immunotherapy.