Josephin Domain Containing 2 (JOSD2) inhibition as Pan-KRAS-mutation-targeting strategy for colorectal cancer
Abstract KRAS is the most common mutated oncogenes in colorectal cancer (CRC), yet effective therapeutic strategies for targeting multiple KRAS mutations remained challenging. The prolonged protein stability of KRAS mutants contribute to their robust tumor-promoting effects, but the underlying mecha...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58923-y |
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| _version_ | 1850181595322908672 |
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| author | Tao Yuan Yue Liu Ruilin Wu Meijia Qian Weihua Wang Yonghao Li Hongdao Zhu Jia’er Wang Fujing Ge Chenming Zeng Xiaoyang Dai Ronggui Hu Tianhua Zhou Qiaojun He Hong Zhu Bo Yang |
| author_facet | Tao Yuan Yue Liu Ruilin Wu Meijia Qian Weihua Wang Yonghao Li Hongdao Zhu Jia’er Wang Fujing Ge Chenming Zeng Xiaoyang Dai Ronggui Hu Tianhua Zhou Qiaojun He Hong Zhu Bo Yang |
| author_sort | Tao Yuan |
| collection | DOAJ |
| description | Abstract KRAS is the most common mutated oncogenes in colorectal cancer (CRC), yet effective therapeutic strategies for targeting multiple KRAS mutations remained challenging. The prolonged protein stability of KRAS mutants contribute to their robust tumor-promoting effects, but the underlying mechanism is elusive. Herein by screening deubiquitinases (DUBs) siRNA library, we identify Josephin domain containing 2 (JOSD2) functions as a potent DUB that regulates the protein stability of KRAS mutants. Mechanistically, JOSD2 directly interacts with and stabilizes KRAS variants across different mutants, by reverting their proteolytic ubiquitination; while KRAS mutants reciprocally inhibit the catalytic activity of CHIP, a bona fide E3 ubiquitin ligase for JOSD2, thus forming a JOSD2/KRAS positive feedback circuit that significantly accelerates KRAS-mutant CRC growth. Inhibition of JOSD2 by RNA interference or its pharmacological inhibitor promotes the polyubiquitination and proteasomal degradation of KRAS mutants, and preferentially impede the growth of KRAS-mutant CRC including patient-derived cells/xenografts/organoids (PDCs/PDXs/PDOs) over that harboring wild-type KRAS. Collectively, this study not only reveals the crucial roles of JOSD2/KRAS positive feedback circuit in KRAS-mutant CRC, but also provides a rationale to target JOSD2 as the promising pan-KRAS-mutation-targeting strategy for the treatment of a broad population of CRC patients with KRAS variant across different mutant types. |
| format | Article |
| id | doaj-art-bf3180cdb03f4cd4ae1906aeb467eab1 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-bf3180cdb03f4cd4ae1906aeb467eab12025-08-20T02:17:52ZengNature PortfolioNature Communications2041-17232025-04-0116111910.1038/s41467-025-58923-yJosephin Domain Containing 2 (JOSD2) inhibition as Pan-KRAS-mutation-targeting strategy for colorectal cancerTao Yuan0Yue Liu1Ruilin Wu2Meijia Qian3Weihua Wang4Yonghao Li5Hongdao Zhu6Jia’er Wang7Fujing Ge8Chenming Zeng9Xiaoyang Dai10Ronggui Hu11Tianhua Zhou12Qiaojun He13Hong Zhu14Bo Yang15Institute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang UniversityInstitute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang UniversityInstitute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang UniversityInstitute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang UniversityInstitute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang UniversityInstitute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang UniversityInstitute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang UniversityInstitute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang UniversityInstitute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang UniversityInnovation Institute for Artificial Intelligence in Medicine, Zhejiang UniversityCenter for Drug Safety Evaluation and Research of Zhejiang UniversitySecond Affiliated Hospital, Zhejiang University School of MedicineDepartment of Cell Biology, Zhejiang University School of MedicineInstitute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang UniversityInstitute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang UniversityInstitute of Pharmacology & Toxicology, Zhejiang Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang UniversityAbstract KRAS is the most common mutated oncogenes in colorectal cancer (CRC), yet effective therapeutic strategies for targeting multiple KRAS mutations remained challenging. The prolonged protein stability of KRAS mutants contribute to their robust tumor-promoting effects, but the underlying mechanism is elusive. Herein by screening deubiquitinases (DUBs) siRNA library, we identify Josephin domain containing 2 (JOSD2) functions as a potent DUB that regulates the protein stability of KRAS mutants. Mechanistically, JOSD2 directly interacts with and stabilizes KRAS variants across different mutants, by reverting their proteolytic ubiquitination; while KRAS mutants reciprocally inhibit the catalytic activity of CHIP, a bona fide E3 ubiquitin ligase for JOSD2, thus forming a JOSD2/KRAS positive feedback circuit that significantly accelerates KRAS-mutant CRC growth. Inhibition of JOSD2 by RNA interference or its pharmacological inhibitor promotes the polyubiquitination and proteasomal degradation of KRAS mutants, and preferentially impede the growth of KRAS-mutant CRC including patient-derived cells/xenografts/organoids (PDCs/PDXs/PDOs) over that harboring wild-type KRAS. Collectively, this study not only reveals the crucial roles of JOSD2/KRAS positive feedback circuit in KRAS-mutant CRC, but also provides a rationale to target JOSD2 as the promising pan-KRAS-mutation-targeting strategy for the treatment of a broad population of CRC patients with KRAS variant across different mutant types.https://doi.org/10.1038/s41467-025-58923-y |
| spellingShingle | Tao Yuan Yue Liu Ruilin Wu Meijia Qian Weihua Wang Yonghao Li Hongdao Zhu Jia’er Wang Fujing Ge Chenming Zeng Xiaoyang Dai Ronggui Hu Tianhua Zhou Qiaojun He Hong Zhu Bo Yang Josephin Domain Containing 2 (JOSD2) inhibition as Pan-KRAS-mutation-targeting strategy for colorectal cancer Nature Communications |
| title | Josephin Domain Containing 2 (JOSD2) inhibition as Pan-KRAS-mutation-targeting strategy for colorectal cancer |
| title_full | Josephin Domain Containing 2 (JOSD2) inhibition as Pan-KRAS-mutation-targeting strategy for colorectal cancer |
| title_fullStr | Josephin Domain Containing 2 (JOSD2) inhibition as Pan-KRAS-mutation-targeting strategy for colorectal cancer |
| title_full_unstemmed | Josephin Domain Containing 2 (JOSD2) inhibition as Pan-KRAS-mutation-targeting strategy for colorectal cancer |
| title_short | Josephin Domain Containing 2 (JOSD2) inhibition as Pan-KRAS-mutation-targeting strategy for colorectal cancer |
| title_sort | josephin domain containing 2 josd2 inhibition as pan kras mutation targeting strategy for colorectal cancer |
| url | https://doi.org/10.1038/s41467-025-58923-y |
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