SNS-023 sensitizes hepatocellular carcinoma to sorafenib by inducing degradation of cancer drivers SIX1 and RPS16  

作　　者：Yuan Liu Wei-yao Kong Cui-fu Yu Zhen-long Shao Qiu-cheng Lei Yuan-fei Deng Geng-xi Cai Xue-fen Zhuang Wen-shuang Sun Shi-gang Wu Rong Wang Xiang Chen Guo-xing Chen Hong-biao Huang Yu-ning Liao 

机构地区：[1]Department of General Surgery,The Sixth Affiliated Hospital of Guangzhou Medical University,Qingyuan People’s Hospital,Qingyuan 511500,China [2]Affiliated Cancer Hospital&Institute of Guangzhou Medical University,Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation,School of Basic Medical Sciences,Guangzhou Medical University,Guangzhou 511436,China [3]Department of Hepatopancreatic Surgery,The First People’s Hospital of Foshan,Foshan 528000,China [4]Department of Pathology,The First People’s Hospital of Foshan,Foshan 528000,China [5]Department of Breast Surgery,The First People’s Hospital of Foshan,Foshan 528000,China [6]Department of Pathology,The Sixth Affiliated Hospital of Guangzhou Medical University,Qingyuan People’s Hospital,Qingyuan 511500,China

出　　处：《Acta Pharmacologica Sinica》2023年第4期853-864,共12页中国药理学报（英文版）

基　　金：supported by National Natural ScienceFoundation of China(82002481,82072810);the open researchfunds fromthe Sixth Affliated Hospitalof Guangzhou Medical University,Q,ingyuan People's Hospital(202011-304,202011-204);the Science and Technology Program of Guangzhou(202102020931);Natural Science Foundation Research Team of Guangdong Province(2018B030312001);Cultivation Program of National Natural Science Foundation for Distinguished Young Scholars of Guangzhou Medical University(JP2022002);Discipline Construction Funds of GuangzhouMedicalUniversity(JCXKJS2021C04,JCXKJS2021D03,and JCXKJS2021D06);Special Fund of Foshan Summit Plan(2020G010)and Guangzhou Key Medical Discipline Construction Project Fund.

摘　　要：Hepatocellular carcinoma(HCC)remains challenging due to the lack of efficient therapy.Promoting degradation of certain cancer drivers has become an innovative therapy.The nuclear transcription factor sine oculis homeobox 1(SIX1)is a key driver for the progression of HCC.Here,we explored the molecular mechanisms of ubiquitination of SIX1 and whether targeting SIX1 degradation might represent a potential strategy for HCC therapy.Through detecting the ubiquitination level of SIX1 in clinical HCC tissues and analyzing TCGA and GEPIA databases,we found that ubiquitin specific peptidase 1(USP1),a deubiquitinating enzyme,contributed to the lower ubiquitination and high protein level of SIX1 in HCC tissues.In HepG2 and Hep3B cells,activation of EGFR-AKT signaling pathway promoted the expression of USP1 and the stability of its substrates,including SIX1 and ribosomal protein S16(RPS16).In contrast,suppression of EGFR with gefitinib or knockdown of USP1 restrained EGF-elevated levels of SIX1 and RPS16.We further revealed that SNS-023(formerly known as BMS-387032)induced degradation of SIX1 and RPS16,whereas this process was reversed by reactivation of EGFR-AKT pathway or overexpression of USP1.Consequently,inactivation of the EGFR-AKT-USP1 axis with SNS-032 led to cell cycle arrest,apoptosis,and suppression of cell proliferation and migration in HCC.Moreover,we showed that sorafenib combined with SNS-032 or gefitinib synergistically inhibited the growth of Hep3B xenografts in vivo.Overall,we identify that both SIX1 and RPS16 are crucial substrates for the EGFR-AKT-USP1 axis-driven growth of HCC,suggesting a potential anti-HCC strategy from a novel perspective.

关 键 词：SNS-023 ML323 SORAFENIB GEFITINIB MK2206 

分 类 号：R735.7[医药卫生—肿瘤]