Yu Aijuan, Yu Pengcheng, Zhu Yuwen, Zhu Rui, Sun Renqiang, Ye Dan, Yu Fa-Xing
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.
Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Oncogene. 2023 Oct;42(43):3182-3193. doi: 10.1038/s41388-023-02831-2. Epub 2023 Sep 9.
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.
碳水化合物反应元件（ChoRE）结合蛋白（ChREBP）及其结合伴侣Max样蛋白X（MLX）在富含葡萄糖的条件下介导脂肪生成基因的转录。葡萄糖和脂质代谢失调在包括肝细胞癌（HCC）在内的癌症中经常发生。然而，目前尚不清楚葡萄糖诱导的脂肪生成程序是否在HCC的发展中起作用。在这里，我们表明MLX在HCC标本中的表达升高，而MLX表达的下调抑制HCC细胞的增殖。在小鼠中，肝脏特异性敲除Mlx会导致脂肪生成基因的表达和循环中的脂质水平显著降低。有趣的是，在没有Mlx的情况下，多种HCC模型中的肿瘤发展，如二乙基亚硝胺（DEN）处理和致癌基因（AKT/RAS或CTNNB1/RAS）的流体动力学注射，均被强烈阻断。然而，高脂饮食可以部分恢复Mlx缺陷肝脏中的肿瘤发生，表明脂质合成在HCC发展中起关键作用。此外，通过腺相关病毒肝脏特异性表达显性负性MLX（dnMLX）可有效阻断小鼠的肿瘤发生。因此，葡萄糖诱导的脂肪生成程序是HCC发展所必需的，并且ChREBP：MLX转录因子可作为癌症治疗的潜在靶点。
