Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development
Abstract Cancers with activating mutations of KRAS show a high prevalence but remain intractable, requiring innovative strategies to overcome the poor targetability of KRAS. Here, we report that KRAS expression is post-translationally up-regulated through deubiquitination when the scaffolding functi...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54476-8 |
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| author | Han Koo Kyung Chan Park Hyun Ahm Sohn Minho Kang Dong Joon Kim Zee-Yong Park Sehoon Park Sang Hyun Min Seong-Hwan Park Yeon-Mi You Yohan Han Bo-Kyung Kim Chul-Ho Lee Yeon-Soo Kim Sang J. Chung Young Il Yeom Dong Chul Lee |
| author_facet | Han Koo Kyung Chan Park Hyun Ahm Sohn Minho Kang Dong Joon Kim Zee-Yong Park Sehoon Park Sang Hyun Min Seong-Hwan Park Yeon-Mi You Yohan Han Bo-Kyung Kim Chul-Ho Lee Yeon-Soo Kim Sang J. Chung Young Il Yeom Dong Chul Lee |
| author_sort | Han Koo |
| collection | DOAJ |
| description | Abstract Cancers with activating mutations of KRAS show a high prevalence but remain intractable, requiring innovative strategies to overcome the poor targetability of KRAS. Here, we report that KRAS expression is post-translationally up-regulated through deubiquitination when the scaffolding function of NDRG3 (N-Myc downstream-regulated gene 3) promotes specific interaction between KRAS and a deubiquitinating enzyme, USP9X. In KRAS-mutant cancer cells KRAS protein expression, downstream signaling, and cell growth are highly dependent on NDRG3. In conditional KrasG12D knock-in mouse models of pancreatic ductal adenocarcinoma, Ndrg3 depletion abolishes Kras protein expression and suppresses intraepithelial neoplasia formation in pancreas. Mechanistically, KRAS protein binds to the C-terminal serine/threonine-rich region of NDRG3, subsequently going through deubiquitination by USP9X recruited to the complex. This interaction can be disrupted in a dominant-negative manner by a C-terminal NDRG3 fragment that binds KRAS but is defective in USP9X binding, highly suppressing KRAS protein expression and KRAS-driven cell growth. In summary, KRAS-driven cancer development critically depends on the deubiquitination of KRAS protein mediated by USP9X/NDRG3, and KRAS-addicted cancers could be effectively targeted by inhibiting the KRAS-NDRG3 interaction. |
| format | Article |
| id | doaj-art-c9c95e6900c648b1a88076dc34e1bc84 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c9c95e6900c648b1a88076dc34e1bc842025-01-19T12:30:37ZengNature PortfolioNature Communications2041-17232025-01-0116111710.1038/s41467-024-54476-8Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer developmentHan Koo0Kyung Chan Park1Hyun Ahm Sohn2Minho Kang3Dong Joon Kim4Zee-Yong Park5Sehoon Park6Sang Hyun Min7Seong-Hwan Park8Yeon-Mi You9Yohan Han10Bo-Kyung Kim11Chul-Ho Lee12Yeon-Soo Kim13Sang J. Chung14Young Il Yeom15Dong Chul Lee16Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Department of Microbiology, College of Medicine, Dankook UniversitySchool of Life Sciences, Gwangju Institute of Science and TechnologySchool of Life Sciences, Gwangju Institute of Science and TechnologyDepartment of Innovative Pharmaceutical Sciences, Kyungpook National UniversityPersonalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Department of Functional Genomics, KRIBB School of Bioscience, University of Science and TechnologyGraduate School of New Drug Discovery and Development, Chungnam National UniversityDepartment of Biopharmaceutical Convergence, School of Pharmacy, Sungkyunkwan UniversityPersonalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Abstract Cancers with activating mutations of KRAS show a high prevalence but remain intractable, requiring innovative strategies to overcome the poor targetability of KRAS. Here, we report that KRAS expression is post-translationally up-regulated through deubiquitination when the scaffolding function of NDRG3 (N-Myc downstream-regulated gene 3) promotes specific interaction between KRAS and a deubiquitinating enzyme, USP9X. In KRAS-mutant cancer cells KRAS protein expression, downstream signaling, and cell growth are highly dependent on NDRG3. In conditional KrasG12D knock-in mouse models of pancreatic ductal adenocarcinoma, Ndrg3 depletion abolishes Kras protein expression and suppresses intraepithelial neoplasia formation in pancreas. Mechanistically, KRAS protein binds to the C-terminal serine/threonine-rich region of NDRG3, subsequently going through deubiquitination by USP9X recruited to the complex. This interaction can be disrupted in a dominant-negative manner by a C-terminal NDRG3 fragment that binds KRAS but is defective in USP9X binding, highly suppressing KRAS protein expression and KRAS-driven cell growth. In summary, KRAS-driven cancer development critically depends on the deubiquitination of KRAS protein mediated by USP9X/NDRG3, and KRAS-addicted cancers could be effectively targeted by inhibiting the KRAS-NDRG3 interaction.https://doi.org/10.1038/s41467-024-54476-8 |
| spellingShingle | Han Koo Kyung Chan Park Hyun Ahm Sohn Minho Kang Dong Joon Kim Zee-Yong Park Sehoon Park Sang Hyun Min Seong-Hwan Park Yeon-Mi You Yohan Han Bo-Kyung Kim Chul-Ho Lee Yeon-Soo Kim Sang J. Chung Young Il Yeom Dong Chul Lee Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development Nature Communications |
| title | Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development |
| title_full | Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development |
| title_fullStr | Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development |
| title_full_unstemmed | Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development |
| title_short | Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development |
| title_sort | anti proteolytic regulation of kras by usp9x ndrg3 in kras driven cancer development |
| url | https://doi.org/10.1038/s41467-024-54476-8 |
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