Tuftelin 1 Facilitates Hepatocellular Carcinoma Progression through Regulation of Lipogenesis and Focal Adhesion Maturation
Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, characterized by a poor prognosis globally. Recent evidence highlights the pivotal role of lipid de novo synthesis in HCC progression, although its regulatory mechanisms remain incompletely understood. In this study, we identified tuftelin 1 (TUFT1), an acidic phosphorylated glycoprotein with secretory capacity, as being significantly upregulated in HCC. TUFT1 expression showed a strong correlation with patient survival and malignancy characteristics.
Using database analysis and experimental validation, we found that TUFT1 is closely linked to fatty acid metabolism and promotes lipid accumulation in HCC cells. Notably, TUFT1 interacts with CREB1, a transcription factor involved in hepatic lipid metabolism, modulating its activity and the transcription of key lipogenic enzymes. TUFT1 markedly enhanced HCC cell proliferation, an effect partially reversed by KG-501, a CREB1 inhibitor.
Additionally, TUFT1 promoted HCC cell invasion in vitro, likely through its interaction with zyxin (ZYX), a zinc-binding phosphoprotein crucial for the formation of mature focal adhesions. TUFT1 was found to inhibit ZYX expression and its recruitment to focal complexes in HCC cells.
Overall, this study reveals novel regulatory mechanisms by which TUFT1 drives lipogenesis, cell proliferation, and invasion in HCC, offering potential therapeutic insights for targeting this pathway.