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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The raw data of wild type and Mlx KO RNA-seq were deposited in the National Genomics Data Center (PRJCA019322).
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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.
The authors declare no competing interests.
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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