Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating β-catenin
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 poo...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723015231 |
| _version_ | 1827609582095040512 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yanguan Guo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T07:35:30Z |
| format | Article |
| id | doaj.art-9e805ddd99bd46528a03270fc5c0833e |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-09T07:35:30Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-9e805ddd99bd46528a03270fc5c0833e2023-12-03T05:41:04ZengElsevierCell Reports2211-12472023-12-014212113511Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating β-cateninYanguan Guo0Jiaxin Tian1Yongjian Guo2Cong Wang3Congcong Chen4Songwang Cai5Wenliang Yu6Binghe Sun7Jin Yan8Zhonghua Li9Jun Fan10Qi Qi11Dongmei Zhang12Weilin Jin13Zichun Hua14Guo Chen15School 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. ChinaSchool of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. ChinaSchool of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. ChinaSchool of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. ChinaDepartment of General Surgery and Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, P.R. ChinaDepartment of General Surgery and Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, P.R. ChinaSchool of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. ChinaSchool of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. ChinaSchool of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. ChinaSchool of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. ChinaDepartment of Medical Biochemistry, Molecular Biology and Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, P.R. ChinaDepartment of Medical Biochemistry, Molecular Biology and Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, P.R. ChinaCollege of Pharmacy, Jinan University, Guangzhou 510632, P.R. ChinaMedical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou 730000, P.R. ChinaSchool of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China; School of Life Sciences, Nanjing University, Nanjing 210023, P.R. China; Corresponding authorSchool 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723015231CP: Cancer |
| spellingShingle | 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 Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating β-catenin Cell Reports CP: Cancer |
| title | Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating β-catenin |
| title_full | Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating β-catenin |
| title_fullStr | Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating β-catenin |
| title_full_unstemmed | Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating β-catenin |
| title_short | Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating β-catenin |
| title_sort | oncogenic kras effector usp13 promotes metastasis in non small cell lung cancer through deubiquitinating β catenin |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723015231 |
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