FTO Promotes Hepatocellular Carcinoma Progression by Mediating m6A Modification of BUB1 and Targeting TGF-βR1 to Activate the TGF-β Signaling Pathway
Year: 2025
Type: article
Abstract: Background and Aims: Fat mass and obesity-associated protein (FTO) has been linked to various cancers, though its role in hepatocellular carcinoma (HCC) remains unclear. This study aimed to investigate FTO expression, its clinical relevance, functional role in HCC progression, and the underlying molecular mechanisms. Methods: studies in nude mice were conducted to evaluate tumor growth following FTO knockdown. Results: FTO was significantly upregulated in HCC tissues compared to normal liver tissues, with higher expression observed in advanced tumor-node-metastasis stages and metastatic HCC. Elevated FTO correlated with poor overall survival in patients. Silencing FTO decreased HCC cell proliferation, colony formation, invasion, epithelial-mesenchymal transition, and tumor growth in nude mice. Mechanistically, FTO downregulation led to increased m6A modification of BUB1 mRNA, thereby promoting its degradation via the YTH domain family 2-dependent pathway and reducing BUB1 protein levels. Additionally, BUB1 physically interacted with TGF-βR1, activating downstream TGF-β signaling. Conclusions: FTO is overexpressed in HCC and is associated with poor clinical outcomes. Mechanistically, FTO promotes HCC progression by stabilizing BUB1 mRNA through an m6A-YTH domain family 2-dependent pathway, which activates TGF-β signaling. Targeting the FTO-BUB1-TGF-βR1 regulatory network may offer a promising therapeutic strategy for HCC.
Authors: Lin Zhang, Li Gan, Yuru Lin, Zhechuan Mei, Shengtao Liao
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
Awards: G3026213867, G5712703136
OpenAlex ID: W4409588742