SKP2 ubiquitylation modifies IDH1 to regulate hepatoblastoma cell cycle and glucose metabolism.
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PURPOSE: Hepatoblastoma (HB) is the most common and lethal malignant solid tumor of liver in children. Targeting the progression of tumor glucose metabolism represents a promising strategy to attenuate the tumor promoting microenvironment. The Warburg effect, a hallmark metabolic feature of tumor cells, plays an important role in mediating tumorigenesis and progression. In this study, we elucidated the critical role of SKP2 in the development of hepatoblastoma. Materials and Methods SKP2 was identified by GEO database to play an important role in hepatoblastoma. The high expression of SKP2 in the tumor was confirmed by hepatoblastoma biopsy. HepG2 and Huh6 cell lines and tumor-bearing mouse models were used to investigate the oncogenic role of SKP2. The co-immunoprecipitation (Co-IP) technique was used to confirm that SKP2 ubiquitylation modifies IDH1 in hepatoblastoma. By ELISA, flow cytometry and confocal microscopy, we demonstrated that SKP2 regulated glucose metabolism through IDH1 in hepatoblastoma cells. Results Overexpression of SKP2 is strongly associated with poor prognosis in HB patients. In addition, SKP2 not only directly regulates the malignant biological behaviors of tumor cells, such as proliferation, migration and invasion, but also regulates the glucose metabolism of tumor cells through ubiquitylation of IDH1. Our in vitro experiments demonstrate that the regulation of SKP2 significantly alters the biological behavior of HB tumor cells. Notably, we further revealed that IDH1 inhibitors can effectively suppress the accumulation of IDH1 in SKP2-suppressed hepatoblastoma cells by IDH1 inhibitors, thereby reversing the tumor suppressive effect induced by SKP2 inhibitors. Conclusion This study highlights the central role of SKP2 in driving the malignant progression of HB, primarily through the ubiquitylation-mediated regulation of IDH1. These findings establish SKP2 as a highly promising biomarker and therapeutic target for the treatment of anti-hepatoblastoma. MATERIALS AND METHODS: SKP2 was identified by GEO database to play an important role in hepatoblastoma. The high expression of SKP2 in the tumor was confirmed by hepatoblastoma biopsy. HepG2 and Huh6 cell lines and tumor-bearing mouse models were used to investigate the oncogenic role of SKP2. The co-immunoprecipitation (Co-IP) technique was used to confirm that SKP2 ubiquitylation modifies IDH1 in hepatoblastoma. By ELISA, flow cytometry and confocal microscopy, we demonstrated that SKP2 regulated glucose metabolism through IDH1 in hepatoblastoma cells. RESULTS: Overexpression of SKP2 is strongly associated with poor prognosis in HB patients. In addition, SKP2 not only directly regulates the malignant biological behaviors of tumor cells, such as proliferation, migration and invasion, but also regulates the glucose metabolism of tumor cells through ubiquitylation of IDH1. Our in vitro experiments demonstrate that the regulation of SKP2 significantly alters the biological behavior of HB tumor cells. Notably, we further revealed that IDH1 inhibitors can effectively suppress the accumulation of IDH1 in SKP2-suppressed hepatoblastoma cells by IDH1 inhibitors, thereby reversing the tumor suppressive effect induced by SKP2 inhibitors. CONCLUSION: This study highlights the central role of SKP2 in driving the malignant progression of HB, primarily through the ubiquitylation-mediated regulation of IDH1. These findings establish SKP2 as a highly promising biomarker and therapeutic target for the treatment of anti-hepatoblastoma.