Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata, 997-0052, Japan.
Commun Biol. 2024 Apr 29;7(1):510. doi: 10.1038/s42003-024-06202-9.
Deregulation of the Wnt/β-catenin pathway is associated with the development of human cancer including colorectal and liver cancer. Although we previously showed that histidine ammonia lyase (HAL) was transcriptionally reduced by the β-catenin/TCF complex in liver cancer cells, the mechanism(s) of its down-regulation by the complex remain to be clarified. In this study, we search for the transcription factor(s) regulating HAL, and identify CEBPA and FOXA1, two factors whose expression is suppressed by the knockdown of β-catenin or TCF7L2. In addition, RNA-seq analysis coupled with genome-wide mapping of CEBPA- and FOXA1-binding regions reveals that these two factors also increase the expression of arginase 1 (ARG1) that catalyzes the hydrolysis of arginine. Metabolome analysis discloses that activated Wnt signaling augments intracellular concentrations of histidine and arginine, and that the signal also increases the level of lactic acid suggesting the induction of the Warburg effect in liver cancer cells. Further analysis reveals that the levels of metabolites of the urea cycle and genes coding its related enzymes are also modulated by the Wnt signaling. These findings shed light on the altered cellular metabolism in the liver by the Wnt/β-catenin pathway through the suppression of liver-enriched transcription factors including CEBPA and FOXA1.
Wnt/β-catenin 通路的失调与包括结直肠癌和肝癌在内的人类癌症的发展有关。虽然我们之前已经表明，组氨酸氨裂解酶（HAL）在肝癌细胞中被β-catenin/TCF 复合物转录下调，但该复合物下调其的机制仍需阐明。在这项研究中，我们寻找调节 HAL 的转录因子，并确定 CEBPA 和 FOXA1 这两个因子，它们的表达受β-catenin 或 TCF7L2 的敲低抑制。此外，结合 CEBPA 和 FOXA1 结合区域的全基因组映射的 RNA-seq 分析表明，这两个因子也增加了精氨酸酶 1（ARG1）的表达，ARG1 催化精氨酸的水解。代谢组学分析揭示，激活的 Wnt 信号增加了组氨酸和精氨酸的细胞内浓度，并且该信号还增加了乳酸水平，表明肝癌细胞中诱导了瓦博格效应。进一步的分析表明，尿素循环的代谢物水平及其相关酶的基因编码也受到 Wnt 信号的调节。这些发现揭示了 Wnt/β-catenin 通路通过抑制包括 CEBPA 和 FOXA1 在内的肝丰富转录因子，改变了肝脏的细胞代谢。
