Oncogenic β-catenin stimulation of AKT2-CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer
Fangming Liu 1, Xiaochen Gai 1, Yuting Wu
1, Baohui Zhang 2, Xiaoyu Wu 3, Rongrong Cheng 3, Bufu Tang 4, Kezhuo Shang 1,
Na Zhao 1, Weiwei Deng 1, Jie Chen 5, Zhengyi Zhang 6 7, Song Gu 8, Liang Zheng
3 9 10, Hongbing Zhang 1
Proc Natl Acad Sci U S A. 2022 Sep
27;119(39):e2202157119. doi: 10.1073/pnas.2202157119. Epub 2022 Sep 19.
PMID: 36122209
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.