Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating β-catenin
Yanguan Guo,
Jiaxin Tian,
Yongjian Guo,
Cong Wang,
Congcong Chen,
Songwang Cai,
Wenliang Yu,
Binghe Sun,
Jin Yan,
Zhonghua Li,
Jun Fan,
Qi Qi,
Dongmei Zhang,
Weilin Jin,
Zichun Hua,
Guo Chen
Affiliations
Yanguan Guo
School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China; Department of General Surgery and Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, P.R. China
Jiaxin Tian
School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China
Yongjian Guo
School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China
Cong Wang
School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China
Congcong Chen
Department of General Surgery and Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, P.R. China
Songwang Cai
Department of General Surgery and Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, P.R. China
Wenliang Yu
School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China
Binghe Sun
School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China
Jin Yan
School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China
Zhonghua Li
School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China
Jun Fan
Department of Medical Biochemistry, Molecular Biology and Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, P.R. China
Qi Qi
Department of Medical Biochemistry, Molecular Biology and Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, P.R. China
Dongmei Zhang
College of Pharmacy, Jinan University, Guangzhou 510632, P.R. China
Weilin Jin
Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou 730000, P.R. China
Zichun Hua
School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China; School of Life Sciences, Nanjing University, Nanjing 210023, P.R. China; Corresponding author
Guo Chen
School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China; Department of Medical Biochemistry, Molecular Biology and Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, P.R. China; Corresponding author
Summary: KRAS mutations are frequently detected in non-small cell lung cancers (NSCLCs). Although covalent KRASG12C inhibitors have been developed to treat KRASG12C-mutant cancers, effective treatments are still lacking for other KRAS-mutant NSCLCs. Thus, identifying a KRAS effector that confers poor prognosis would provide an alternative strategy for the treatment of KRAS-driven cancers. Here, we show that KRAS drives expression of deubiquitinase USP13 through Ras-responsive element-binding protein 1 (RREB1). Elevated USP13 promotes KRAS-mutant NSCLC metastasis, which is associated with poor prognosis in NSCLC patients. Mechanistically, USP13 interacts with and removes the K63-linked polyubiquitination of β-catenin at lysine 508, which enhances the binding between β-catenin and transcription factor TCF4. Importantly, we identify 2-methoxyestradiol as an effective inhibitor for USP13 from a natural compound library, and it could potently suppress the metastasis of KRAS-mutant NSCLC cells in vitro and in vivo. These findings identify USP13 as a therapeutic target for metastatic NSCLC with KRAS mutations.
