PDF(Pubmed)
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.
摘要：
N6-甲基腺苷(m6A)修饰通过影响肿瘤微环境(TME)来协调癌症形成和进展。对于肝细胞癌（HCC），免疫逃避和血管生成是其TME的特征。YTHN6-甲基腺苷RNA结合蛋白2（YTHDF2）的作用，作为一名m6读者，在调节HCCTME方面还没有完全理解。在这里，发现YTHDF2启动子区的三甲基化组蛋白H3赖氨酸4和H3赖氨酸27乙酰化修饰增强了其在HCC中的表达，并在HCC中上调YTHDF2预测预后较差。动物实验表明，Ythdf2耗竭抑制自发性肝癌形成，而其过度表达促进异种移植HCC进展。机械上,YTHDF2识别ETS变异转录因子5（ETV5）mRNA的5'非翻译区中的m6A修饰，并招募真核翻译起始因子3亚基B以促进其翻译。升高的ETV5表达诱导程序性死亡配体-1和血管内皮生长因子A的转录,从而促进HCC免疫逃避和血管生成。通过含有小干扰RNA的适体/脂质体靶向YTHDF2成功地抑制HCC免疫逃避和血管生成。一起,这一发现揭示了YTHDF2在HCC预后和靶向治疗中的潜在应用。
