FTO promotes hepatocellular carcinoma progression by mediating m6A modification of BUB1 and targeting TGF-βR1 to activate the TGF-β signaling pathway

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

Quantitative reverse-transcription polymerase chain reaction and immunohistochemical analysis were used to assess FTO expression in HCC. Functional assays, including proliferation, invasion, and epithelial-mesenchymal transition studies, were conducted using HCC cell lines with FTO knockdown. N6-methyladenosine (m6A) RNA immunoprecipitation and RNA stability assays further elucidated the role of FTO in BUB1 mRNA methylation and stability. Co-immunoprecipitation studies were employed to confirm the interaction between BUB1 and TGF-βR1. In vivo 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

This study highlights the critical function of FTO in orchestrating m6A-dependent regulation of BUB1 and the subsequent amplification of TGF-β signaling in HCC. By revealing how FTO-driven BUB1 upregulation fosters malignant phenotypes, specifically enhancing proliferation, EMT, and tumor invasiveness, our work offers new perspectives for targeting epitranscriptomic modifications in liver cancer. Further research on FTO inhibitors (e.g., FB23-2, Meclofenamate Sodium, Rhein, and Dac51), along with detailed characterization of the BUB1–TGF-βR1 axis, could yield novel therapeutic strategies to abrogate HCC progression and improve patient survival.

Full text

https://www.xiahepublishing.com/2310-8819/JCTH-2025-00007

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

Follow us on X: @xiahepublishing

Follow us on LinkedIn: Xia & He Publishing Inc.