1. Oncogenic β-catenin stimulation of AKT2–CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer
- Author
-
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, and Zhang, Hongbing
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Liver Cancer ,Genetics ,Rare Diseases ,Chronic Liver Disease and Cirrhosis ,Cancer ,Liver Disease ,Digestive Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Animals ,Aspartic Acid ,Carcinogenesis ,Dihydroorotase ,Drug Delivery Systems ,Ligases ,Liver Neoplasms ,Mice ,Nucleotides ,Phosphates ,Proto-Oncogene Proteins c-akt ,Pyrimidines ,beta Catenin ,beta-catenin ,CAD ,AKT2 ,pyrimidine synthesis ,liver cancer ,β-catenin - Abstract
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.
- Published
- 2022