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Oncogenic β-catenin stimulation of AKT2–CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer

  • Liu, Fangming
  • Gai, Xiaochen
  • Wu, Yuting
  • Zhang, Baohui
  • Wu, Xiaoyu
  • Cheng, Rongrong
  • Tang, Bufu
  • Shang, Kezhuo
  • Zhao, Na
  • Deng, Weiwei
  • Chen, Jie
  • Zhang, Zhengyi
  • Gu, Song
  • Zheng, Liang
  • Zhang, Hongbing
Publication Date
Sep 27, 2022
eScholarship - University of California
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CTNNB1, encoding β-catenin protein, is the most frequently altered proto-oncogene in hepatic neoplasms. In this study, we studied the significance and pathological mechanism of CTNNB1 gain-of-function mutations in hepatocarcinogenesis. Activated β-catenin not only triggered hepatic tumorigenesis but also exacerbated Tp53 deletion or hepatitis B virus infection-mediated liver cancer development in mouse models. Using untargeted metabolomic profiling, we identified boosted de novo pyrimidine synthesis as the major metabolic aberration in β-catenin mutant cell lines and livers. Oncogenic β-catenin transcriptionally stimulated AKT2, which then phosphorylated the rate-limiting de novo pyrimidine synthesis enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase) on S1406 and S1859 to potentiate nucleotide synthesis. Moreover, inhibition of β-catenin/AKT2-stimulated pyrimidine synthesis axis preferentially repressed β-catenin mutant cell proliferation and tumor formation. Therefore, β-catenin active mutations are oncogenic in various preclinical liver cancer models. Stimulation of β-catenin/AKT2/CAD signaling cascade on pyrimidine synthesis is an essential and druggable vulnerability for β-catenin mutant liver cancer.

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