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

作　　者：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 

机构地区：[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 [4]Department of Oncology,Shanghai Medical College,Fudan University,Shanghai 200032,China [5]State Key Laboratory of Medical Neurobiology,Fudan University,Shanghai 200032,China

出　　处：《National Science Review》2022年第5期115-124,共10页国家科学评论（英文版）

基　　金：supported by the Ministry of Science and Technology of China(2020YFA0803400/2020YFA0803402 and 2019YFA0801703);the National Natural Science Foundation of China(81790250/81790253,9195920,8187224,81872240,81802745 and 82002951);the Innovation Program of the Shanghai Municipal Education Commission(N173606);the China Postdoctoral Science Foundation(2021M690676)。

摘　　要：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^(G12 D/+);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-eIF2αpathway 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.

关 键 词：USP1 DEUBIQUITYLATION BCAT2 PANIN PDAC 

分 类 号：R735.9[医药卫生—肿瘤]