YTHDF2 Is a Therapeutic Target for HCC by Suppressing Immune Evasion and Angiogenesis Through ETV5/PD-L1/VEGFA Axis
Jingyuan Wen1,2,3, Lin Xue1,2,3, Yi Wei1,2,3
1Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Abstract:
N6-methyladenosine (m6A) modification orchestrates cancer formation and progression by affecting the tumor microenvironment (TME). For hepatocellular carcinoma (HCC), immune evasion and angiogenesis are characteristic features of its TME. The role of YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), as an m6A reader, in regulating HCC TME are not fully understood. Herein, it is discovered that trimethylated histone H3 lysine 4 and H3 lysine 27 acetylation modification in the promoter region of YTHDF2 enhanced its expression in HCC, and upregulated YTHDF2 in HCC predicted a worse prognosis. Animal experiments demonstrated that Ythdf2 depletion inhibited spontaneous HCC formation, while its overexpression promoted xenografted HCC progression. Mechanistically, YTHDF2 recognized the m6A modification in the 5'-untranslational region of ETS variant transcription factor 5 (ETV5) mRNA and recruited eukaryotic translation initiation factor 3 subunit B to facilitate its translation. Elevated ETV5 expression induced the transcription of programmed death ligand-1 and vascular endothelial growth factor A, thereby promoting HCC immune evasion and angiogenesis. Targeting YTHDF2 via small interference RNA-containing aptamer/liposomes successfully both inhibited HCC immune evasion and angiogenesis. Together, this findings reveal the potential application of YTHDF2 in HCC prognosis and targeted treatment.
Insights
YTHDF2 protein promotes hepatocellular carcinoma (HCC) by enhancing immune evasion and angiogenesis. Inhibiting YTHDF2 shows potential for HCC treatment and improving patient prognosis.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- N6-methyladenosine (m6A) modification influences tumor microenvironment (TME) in cancer.
- Hepatocellular carcinoma (HCC) TME is characterized by immune evasion and angiogenesis.
- The role of YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) in HCC TME requires further elucidation.
Purpose of the Study:
- To investigate the role of YTHDF2 in regulating HCC TME.
- To explore the prognostic value of YTHDF2 in HCC.
- To evaluate YTHDF2 as a therapeutic target for HCC.
Main Methods:
- Analysis of histone modifications (H3K4me3, H3K27ac) in the YTHDF2 promoter region.
- In vivo studies using Ythdf2 knockout and overexpression models in HCC.
- Mechanistic studies involving m6A-modified ETV5 mRNA and its downstream targets (PD-L1, VEGF-A).
- In vivo therapeutic evaluation using YTHDF2-targeting liposomal small interfering RNA.
Main Results:
- YTHDF2 expression is enhanced by H3K4me3 and H3K27ac modifications in HCC, correlating with poor prognosis.
- Ythdf2 depletion inhibited HCC formation, while overexpression promoted tumor progression.
- YTHDF2 facilitates ETV5 translation via m6A recognition, leading to increased PD-L1 and VEGF-A expression.
- Targeting YTHDF2 effectively inhibited HCC immune evasion and angiogenesis in vivo.
Conclusions:
- YTHDF2 plays a critical role in promoting HCC progression by modulating immune evasion and angiogenesis.
- YTHDF2 is a potential prognostic biomarker and therapeutic target for HCC.
- Targeting YTHDF2 offers a promising strategy for HCC treatment.
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