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Glucose-induced and ChREBP: MLX-mediated lipogenic program promotes hepatocellular carcinoma development

Oncogene volume 42, pages 3182–3193 (2023)Cite this article

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Abstract

The Carbohydrate Response Element (ChoRE) Binding Protein (ChREBP) and its binding partner Max-like protein X (MLX) mediate transcription of lipogenic genes under glucose-rich conditions. Dysregulation of glucose and lipid metabolism frequently occurs in cancers, including Hepatocellular Carcinomas (HCCs). However, it is currently unclear whether the glucose-induced lipogenic program plays a role in the development of HCCs. Here, we show that MLX expression is elevated in HCC specimens and downregulation of MLX expression inhibits proliferation of HCC cells. In mice, liver-specific knockout of Mlx results in dramatic decrease in the expression of lipogenic genes and lipid levels in circulation. Interestingly, in the absence of Mlx, the development of tumors in multiple HCC models, such as diethylnitrosamine (DEN) treatment and hydrodynamic injection of oncogenes (AKT/RAS or CTNNB1/RAS), is robustly blocked. However, a high-fat diet can partially restore tumorigenesis in Mlx-deficient livers, indicating a critical role of lipid synthesis in HCC development. In addition, liver-specific expression of a dominant negative MLX (dnMLX) via adeno-associated virus effectively blocks tumorigenesis in mice. Thus, the glucose-induced lipogenic program is required in the development of HCC, and the ChREBP: MLX transcription factors serve as a potential target for cancer therapies.

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Fig. 1: MLX expression is upregulated in clinical and experimental HCC specimens.
Fig. 2: MLX knockout significantly inhibits tumor growth of HCC cells.
Fig. 3: Liver-specific knockout of Mlx disturbs fatty acids homeostasis.
Fig. 4: Liver-specific Mlx deletion inhibits tumorigenesis.
Fig. 5: High-fat diet restored tumorigenesis in Mlx KO mice.
Fig. 6: Hepatocarcinogenesis in mice is repressed dnMLX.

Data availability

The raw data of wild type and Mlx KO RNA-seq were deposited in the National Genomics Data Center (PRJCA019322).

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Acknowledgements

This work was supported by grants from the Ministry of Science and Technology of China (National Key R&D program, 2018YFA0800304 and 2020YFA0803202), the Science and Technology Commission of Shanghai Municipality (21S11905000), and the Shanghai Municipal Health Commission (2022XD049) to FXY. This work is also supported by the Medical Science Data Center in Shanghai Medical College of Fudan University.

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  1. These authors contributed equally: Aijuan Yu, Pengcheng Yu.

Authors and Affiliations

  1. Institute of Pediatrics, Children’s Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, the State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Aijuan Yu, Pengcheng Yu, Yuwen Zhu, Rui Zhu & Fa-Xing Yu

  2. Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Pengcheng Yu

  3. Huashan Hospital and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Renqiang Sun & Dan Ye

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Conceptualization FXY and DY; Experiments and Validation AY, PY, YZ and RZ; Bioinformatics PY, and RS; Visualization, AY, PY, YZ and RS; Writing-Original Draft, AY, PY, and FXY; Writing-Review & Editing FXY; Supervision FXY.

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Yu, A., Yu, P., Zhu, Y. et al. Glucose-induced and ChREBP: MLX-mediated lipogenic program promotes hepatocellular carcinoma development. Oncogene 42, 3182–3193 (2023). https://doi.org/10.1038/s41388-023-02831-2

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