期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：39
DOI：10.1073/pnas.2202157119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
β-Catenin encoding gene
CTNNB1 is known as the most frequently mutated proto-oncogene in liver cancer. We report that active β-catenin is essential in initiation and advancement of hepatocarcinogenesis. As a transcriptional activator of AKT2, β-catenin potentiates AKT2 phosphorylation of CAD, which in return stimulates de novo pyrimidine synthesis and liver cancer development. β-Catenin, AKT2, and pyrimidine synthesis inhibitors are promising therapeutics for the treatment of oncogenic β-catenin–associated cancer.
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.
关键词：enβ-cateninCADAKT2pyrimidine synthesisliver cancer
