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B3galt5 deficiency attenuates hepatocellular carcinoma by suppressing mTOR/p70s6k-mediated glycolysis

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Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies with high morbidity and mortality. Beta-1,3-galactosyltransferase 5 (b3galt5) plays crucial roles in protein glycosylation, but its function in HCC remains unclear. Here, we investigated the role and underlying mechanism of b3galt5 in HCC. We found that b3galt5 is highly expressed and associated with a poor prognosis in HCC patients. In vitro studies showed that b3galt5 promoted the proliferation and survival of HCC cells. We also demonstrated that b3galt5 deficiency suppressed hepatocarcinogenesis in DEN/TCPOBOP-induced HCC. Further investigation confirmed that b3galt5 promoted aerobic glycolysis in HCC. Mechanistically, b3galt5 promoted glycolysis by activating the mTOR/p70s6k pathway through O-linked glycosylation modification on mTOR. Moreover, p70s6k inhibition reduced the expression of key glycolytic enzymes and the glycolysis rate in b3galt5-overexpressing cells. Our study uncovers a novel mechanism by which b3galt5 mediates glycolysis in HCC and highlights the b3galt5-mTOR/p70s6k axis as a potential target for HCC therapy.

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All data generated during this study are included in this published article and its supplementary files.

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Acknowledgements

We are grateful to Prof. Jinhan He at the Department of Pharmacy, West China Hospital of Sichuan University, for sharing the b3galt5-/- mice.

Funding

This work was supported by the National Natural Science Foundation of China (81972745 and 81703072), the Ten Thousand Plan Youth Talent Support Program of Zhejiang Province (ZJWR0108009), and the Zhejiang Medical Innovative Discipline Construction Project-2016.

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Author notes

  1. Xiaoling Zhang and Hao Liu have contributed equally.

Authors and Affiliations

  1. Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qingchun Road, Hangzhou, 310016, Zhejiang, China

    Xiaoling Zhang, Hao Liu, Haidong Wang, Rongjie Zhao, Qian Lu, Yunlong Liu, Yicheng Han,  LuluRen, Hongming Pan & Weidong Han

  2. Department of Medical Oncology, Hangzhou First People’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Xiaoling Zhang

  3. Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Hao Liu & Yunlong Liu

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  1. Xiaoling Zhang
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Contributions

PHM and HWD designed and supervised the project; ZXL, LH, LQ, WHD, LYL, and HYC performed the animal and cell experiments; WHD and ZXL performed the glycosidase experiment, ZRJ analyzed the GEO database; and ZXL, LH, RLL and HWD wrote and edited the manuscript. All of the coauthors reviewed the manuscript.

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Correspondence to Hongming Pan or Weidong Han.

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This study was approved by the Ethics Committee of Zhejiang University. All the animal experiments performed in this study were approved by the Institutional Animal Care and Use Committee of Zhejiang University.

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Zhang, X., Liu, H., Wang, H. et al. B3galt5 deficiency attenuates hepatocellular carcinoma by suppressing mTOR/p70s6k-mediated glycolysis. Cell. Mol. Life Sci. 80, 8 (2023). https://doi.org/10.1007/s00018-022-04601-x

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