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  3. High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-GlcNAcylation via microbiota-derived acetate

High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-GlcNAcylation via microbiota-derived acetate

  • Cell Metab. 2023 Sep 29:S1550-4131(23)00340-6. doi: 10.1016/j.cmet.2023.09.009.
Peng Zhou 1,  Wen-Yi Chang 1,  De-Ao Gong 1,  Jie Xia 1,  Wei Chen 2,  Lu-Yi Huang 1,  Rui Liu 1,  Yi Liu 1,  Chang Chen 3,  Kai Wang 4,  Ni Tang 5,  Ai-Long Huang 6
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China.
  • 2 Shanghai Applied Protein Technology Co., Ltd., Shanghai 201109, China.
  • 3 Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China.
  • 4 Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China. Electronic address: wangkai@cqmu.edu.cn.
  • 5 Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China. Electronic address: nitang@cqmu.edu.cn.
  • 6 Key Laboratory of Molecular Biology for Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China. Electronic address: ahuang@cqmu.edu.cn.
PMID: 37797623 DOI: 10.1016/j.cmet.2023.09.009
Abstract

Emerging studies have addressed the tumor-promoting role of fructose in different cancers. The effects and pathological mechanisms of high dietary fructose on hepatocellular carcinoma (HCC) remain unclear. Here, we examined the effects of fructose supplementation on HCC progression in wild-type C57BL/6 mice using a spontaneous and chemically induced HCC mouse model. We show that elevated uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) and O-GlcNAcylation levels induced by high dietary fructose contribute to HCC progression. Non-targeted metabolomics and stable isotope tracing revealed that under fructose treatment, microbiota-derived acetate upregulates glutamine and UDP-GlcNAc levels and enhances protein O-GlcNAcylation in HCC. Global profiling of O-GlcNAcylation revealed that hyper-O-GlcNAcylation of eukaryotic elongation factor 1A1 promotes cell proliferation and tumor growth. Targeting glutamate-ammonia Ligase or O-linked N-acetylglucosamine transferase (OGT) remarkably impeded HCC progression in mice with high fructose intake. We propose that high dietary fructose promotes HCC progression through microbial acetate-induced hyper-O-GlcNAcylation.

Keywords

GLUL; O-GlcNAcylation; acetate; eEF1A1; fructose; hepatocellular carcinoma.

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