Abstract
O-linked-β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) and ubiquitination are critical posttranslational modifications that regulate tumor development and progression. The continuous progression of the cell cycle is the fundamental cause of tumor proliferation. S-phase kinase-associated protein 2 (SKP2), an important E3 ubiquitin ligase, assumes a pivotal function in the regulation of the cell cycle. However, it is still unclear whether SKP2 is an effector of O-GlcNAcylation that affects tumor progression. In this study, we found that SKP2 interacted with O-GlcNAc transferase (OGT) and was highly O-GlcNAcylated in hepatocellular carcinoma (HCC). Mechanistically, the O-GlcNAcylation at Ser34 stabilized SKP2 by reducing its ubiquitination and degradation mediated by APC-CDH1. Moreover, the O-GlcNAcylation of SKP2 enhanced its binding ability with SKP1, thereby enhancing its ubiquitin ligase function. Consequently, SKP2 facilitated the transition from the G1-S phase of the cell cycle by promoting the ubiquitin degradation of cell cycle-dependent kinase inhibitors p27 and p21. Additionally, targeting the O-GlcNAcylation of SKP2 significantly suppressed the proliferation of HCC. Altogether, our findings reveal that O-GlcNAcylation, a novel posttranslational modification of SKP2, plays a crucial role in promoting HCC proliferation, and targeting the O-GlcNAcylation of SKP2 may become a new therapeutic strategy to impede the progression of HCC.
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Data availability
The original mass spectrometry analysis data of SKP2 O-GlcNAcylation was deposited in the integrated proteome resource (iProX, PXD048234). All relevant data are available from the corresponding author on reasonable request.
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Acknowledgements
We are grateful that Prof. Tongchuan He (University of Chicago, USA) kindly provided the AdEasy system. We also thank Prof. Ding Xue (Tsinghua University, Beijing, China) for supplying the CRISPR/Cas9 system. This work was supported by the China National Natural Science Foundation (Grant nos. 82272975, 82073251, 82072286, 82304288), the National Key Research and Development Program of China (2023YFC23068), the Innovative and Entrepreneurial Team of Chongqing Talents Plan, Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau, 2023DBXM007), the Future Medical Youth Innovation Team of Chongqing Medical University (W0036, W0101), Senior Medical Talents Program of Chongqing for Young and Middle-aged, and the Kuanren talents and DengFeng program of the second affiliated hospital of Chongqing Medical University.
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LYH, NT, and KW designed the experiments; ZQF JXY and ZRZ performed and analyzed the data; ZQF, JXY, ZRZ, and ZC contributed materials and data, and assisted in data analysis; ZQF, JXY, LYH, NT, and KW wrote and edited the paper. All authors have read and approved the article.
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The study protocol for clinical patient samples was approved by the Medical Ethics Committee of Chongqing Medical University (reference number: 2023076). Experimental animals were handled according to guidelines approved by the Institutional Animal Care and Use Committee of Chongqing Medical University (approval number: 20230188). A pathogen-free environment was provided to keep all mice in the Laboratory Animal Center of the Chongqing Medical University.
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Feng, Z., Yin, J., Zhang, Z. et al. O-GlcNAcylation of E3 ubiquitin ligase SKP2 promotes hepatocellular carcinoma proliferation. Oncogene 43, 1149–1159 (2024). https://doi.org/10.1038/s41388-024-02977-7
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DOI: https://doi.org/10.1038/s41388-024-02977-7