YTHDF3-mediated m6A modification of NKD1 regulates hepatocellular carcinoma invasion and metastasis by activating the WNT/β-catenin signaling axis

• Published in: Experimental cell research Vol. 442; no. 1; p. 114192
• Main Authors: Chen, Siyan, Wang, Lumin, Xu, Zhenguo, Chen, Lushan, Li, Quansen, Zhong, Fengjin, Tang, Nanhong, Song, Jun, Zhou, Ruixiang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2024
• Subjects: Hepatocellular carcinoma; Invasion and migration; N6-methyladenosine; NKD1; YTHDF3; Hepatocellular carcinoma; N6-methyladenosine; YTHDF3; Invasion and migration; NKD1; N-methyladenosine
• ISSN: 0014-4827; 1090-2422; 1090-2422
• DOI: 10.1016/j.yexcr.2024.114192

N6-methyladenosine (m6A) alteration is an epigenetic regulator widely involved in the tumorigenicity of hepatocellular carcinoma (HCC). The role of YTH N6-methyladenosine RNA binding protein F3 (YTHDF3), an m6A reader in HCC, requires further investigation. Here, we aim to explore the biological properties of YTHDF3 in HCC and its potential mechanisms. The predictive risk model for HCC was developed by analyzing the expression of genes associated with m6A in HCC using online datasets. WB and qPCR were employed to assess YTHDF3 expression in HCC and its correlation with the disease's clinicopathological characteristics. Both in vitro and in vivo methods were utilized to evaluate the biological effects of YTHDF3 in HCC. The potential targets of YTHDF3 were identified and confirmed using RNA-seq, meRIP-seq, and linear amplification and sequencing of cDNA ends (Lace-seq). We confirmed that YTHDF3 is overexpressed in HCC. Patients with higher YTHDF3 expression had a greater risk of cancer recurrence. In both in vitro and in vivo settings, YTHDF3 boosts the migration and invasion capabilities of HCC cells. Through multi-omics research, we identified YTHDF3's downstream target genes as NKD inhibitors of the WNT signaling pathway 1 (NKD1) and the WNT/β-catenin signaling pathway. With m6A modification, YTHDF3 suppresses the transcription and translation of NKD1. Additionally, NKD1 inhibited tumor growth by blocking the WNT/β-catenin signaling pathway. The investigation found that the oncogene YTHDF3 stimulates the WNT/β-catenin signaling pathway by m6A-dependently suppressing NKD1 expression in HCC cells. Our findings suggest that YTHDF3 regulates hepatocarcinogenesis, providing fresh perspectives on potential biomarkers and therapeutic targets for HCC. •YTHDF3 was overexpressed in HCC.•The risk of cancer recurrence was more significant in HCC patients with increased YTHDF3 expression.•YTHDF3 enhanced the migratory and invasive potential of HCC cells.•YTHDF3 suppressed NKD1's transcription then activated WNT/β-catenin signaling pathway.