Methyltransferase-Like 3-Mediated m6A Methylation of Hsa_circ_0058493 Accelerates Hepatocellular Carcinoma Progression by Binding to YTH Domain-Containing Protein 1.
Methyltransferase-Like 3-Mediated m6A Methylation of Hsa_circ_0058493 Accelerates Hepatocellular Carcinoma Progression by Binding to YTH Domain-Containing Protein 1.
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甲基转移酶样 3 介导的 Hsa_circ_0058493 m6A 甲基化通过与含有 YTH 结构域的蛋白 1 结合加速肝细胞癌进展
DOI：
10.3389/fcell.2021.762588
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发表时间：
2021
影响因子：
5.5
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
Wu A;Hu Y;Xu Y;Xu J;Wang X;Cai A;Liu R;Chen L;Wang F
环状RNA（circRNA）与肝细胞癌（HCC）的进展和预后高度相关。此外，越来越多的证据表明，N6-甲基腺苷 (m6A) 甲基化（一种常见的 RNA 修饰）与恶性肿瘤的进展有关。在这项研究中，一种新的circRNA hsa_circ_0058493被证明在HCC中表达上调，这与HCC患者的预后相关。实验上，hsa_circ_0058493 敲低可抑制体内和体外 HCC 细胞的生长和转移。相反，hsa_circ_0058493在HCC细胞中的过表达在体外却具有相反的效果。机理实验表明hsa_circ_0058493含有m6A甲基化位点，并且甲基转移酶样3（METTL3）介导hsa_circ_0058493的甲基化修饰程度。此外，含有YTH结构域的蛋白1（YTHDC1）可以与hsa_circ_0058493结合并促进其从细胞核到细胞质的细胞内定位。此外，si-METTL3和si-YTHDC1均抑制HCC细胞的生长和转移，而拯救实验证实hsa_circ_0058493的过表达逆转了si-METTL3和si-YTHDC1对HCC细胞的抑制作用。综上所述，本研究探讨了 m6A 修饰的 hsa_circ_0058493 的致癌作用，并发现通过 METTL3-hsa_circ_0058493-YTHDC1 轴加速 HCC 进展，表明这种致命疾病的潜在治疗靶点。
Circular RNAs (circRNAs) are highly correlated with the progression and prognosis of hepatocellular carcinoma (HCC). In addition, mounting evidence has revealed that N6-methyladenosine (m6A) methylation, a common RNA modification, is involved in the progression of malignancies. In this research, a novel circRNA, hsa_circ_0058493, was proven to be upregulated in HCC, which was correlated with the prognosis of HCC patients. Experimentally, hsa_circ_0058493 knockdown suppressed the growth and metastasis of HCC cells in vivo and in vitro. On the contrary, the overexpression of hsa_circ_0058493 in HCC cells had the opposite effect in vitro. Mechanistic experiments revealed that hsa_circ_0058493 contained m6A methylation sites and that methyltransferase-like 3 (METTL3) mediated the degree of methylation modification of hsa_circ_0058493. Furthermore, YTH domain-containing protein 1 (YTHDC1) could bind to hsa_circ_0058493 and promote its intracellular localization from the nucleus to the cytoplasm. In addition, both si-METTL3 and si-YTHDC1 suppressed HCC cell growth and metastasis, whereas rescue experiments confirmed that overexpression of hsa_circ_0058493 inverted the inhibitory effects of si-METTL3 and si-YTHDC1 on HCC cells. Taken together, this study explored the oncogenic role of m6A-modified hsa_circ_0058493 and found to accelerate HCC progression via the METTL3-hsa_circ_0058493-YTHDC1 axis, indicating a potential therapeutic target for this deadly disease.
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