Methyltransferase-Like 3-Mediated m6A Methylation of Hsa_circ_0058493 Accelerates Hepatocellular Carcinoma Progression by Binding to YTH Domain-Containing Protein 1

Anqi Wu; Yuhao Hu; Yao Xu; Jing Xu; Xinyue Wang; Aiting Cai; Ruoyu Liu; Lin Chen; Feng Wang

doi:10.3389/fcell.2021.762588

Methyltransferase-Like 3-Mediated m6A Methylation of Hsa_circ_0058493 Accelerates Hepatocellular Carcinoma Progression by Binding to YTH Domain-Containing Protein 1

Front Cell Dev Biol. 2021 Nov 23:9:762588. doi: 10.3389/fcell.2021.762588. eCollection 2021.

Authors

Anqi Wu¹, Yuhao Hu¹, Yao Xu², Jing Xu³, Xinyue Wang³, Aiting Cai¹, Ruoyu Liu¹, Lin Chen⁴, Feng Wang¹

Affiliations

¹ Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China.
² Department of Laboratory Medicine, The Second Affiliated Hospital of Nantong University, Nantong, China.
³ Department of Laboratory Medicine, School of Public Health, Nantong University, Nantong, China.
⁴ Department of Hepatology Laboratory, Nantong Third Hospital Affiliated to Nantong University, Nantong, China.

Abstract

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.

Keywords: HCC; METTL3; N6-methyladenosine; YTHDC1; circular RNA; hsa_circ_0058493.