Diet high in branched-chain amino acid promotes PDAC development by USP1-mediated BCAT2 stabilization

Jin-Tao Li; Kai-Yue Li; Ying Su; Yuan Shen; Ming-Zhu Lei; Fan Zhang; Miao Yin; Zheng-Jun Chen; Wen-Yu Wen; Wei-Guo Hu; Dan Su; Jia Qu; Qun-Ying Lei

doi:10.1093/nsr/nwab212

Diet high in branched-chain amino acid promotes PDAC development by USP1-mediated BCAT2 stabilization

Natl Sci Rev. 2021 Nov 26;9(5):nwab212. doi: 10.1093/nsr/nwab212. eCollection 2022 May.

Authors

Jin-Tao Li¹, Kai-Yue Li¹, Ying Su¹, Yuan Shen¹, Ming-Zhu Lei¹, Fan Zhang¹, Miao Yin¹, Zheng-Jun Chen², Wen-Yu Wen¹, Wei-Guo Hu¹, Dan Su³, Jia Qu¹, Qun-Ying Lei¹

Affiliations

¹ Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Medical Epigenetics; International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
² State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
³ Cancer Research Institute, Zhejiang Cancer Hospital and Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology of Zhejiang Province, Hangzhou 310022, China.

Abstract

BCAT2-mediated branched-chain amino acid (BCAA) catabolism is critical for pancreatic ductal adenocarcinoma (PDAC) development, especially at an early stage. However, whether a high-BCAA diet promotes PDAC development in vivo, and the underlying mechanism of BCAT2 upregulation, remain undefined. Here, we find that a high-BCAA diet promotes pancreatic intraepithelial neoplasia (PanIN) progression in LSL-Kras^G12D/+ ; Pdx1-Cre (KC) mice. Moreover, we screened with an available deubiquitylase library which contains 31 members of USP family and identified that USP1 deubiquitylates BCAT2 at the K229 site. Furthermore, BCAA increases USP1 protein at the translational level via the GCN2-eIF2α pathway both in vitro and in vivo. More importantly, USP1 inhibition recedes cell proliferation and clone formation in PDAC cells and attenuates pancreas tumor growth in an orthotopic transplanted mice model. Consistently, a positive correlation between USP1 and BCAT2 is found in KC; LSL-Kras^G12D/+ ; p53^flox/+ ; Pdx1-Cre mice and clinical samples. Thus, a therapeutic targeting USP1-BCAT2-BCAA metabolic axis could be considered as a rational strategy for treatment of PDAC and precisive dietary intervention of BCAA has potentially translational significance.

Keywords: BCAT2; PDAC; PanIN; USP1; deubiquitylation.