USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma
| العنوان: | USP28 deletion and small-molecule inhibition destabilizes c-MYC and elicits regression of squamous cell lung carcinoma |
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| المؤلفون: | Malte Gersch, Thomas M. Charlton, Michael J. Clague, Linxiang Lan, Hannah C. Scott, Sylvie Urbé, George Vere, Min Wu, Sunkyu Kim, Stephanos Ioannidis, Claire Heride, Jeffrey D Kearns, Jonathan O'Connell, David Komander, Adan Pinto-Fernandez, E. Josue Ruiz, Emma Nye, Axel Behrens, Benedikt M. Kessler, Andrew P. Turnbull, Marie Katz, Natalia Moncaut, Andreas Damianou, Wojciech W. Krajewski, Neil P. Jones, Christopher J. Dinsmore, Ian Rosewell, Tim Hammonds, David Joseph Guerin, Eva M. Riising, Crystal McKinnon, Clive Da Costa |
| المصدر: | eLife, Vol 10 (2021) eLife |
| بيانات النشر: | eLife Sciences Publications Ltd, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Lung Neoplasms, Gene Expression, medicine.disease_cause, Imaging, Mice, 0302 clinical medicine, Biology (General), Cancer Biology, Human Biology & Physiology, 0303 health sciences, Chemistry, Stem Cells, General Neuroscience, Lung squamous cell carcinoma, Genome Integrity & Repair, Treatment options, General Medicine, Small molecule, 3. Good health, DNA-Binding Proteins, medicine.anatomical_structure, c-MYC, 030220 oncology & carcinogenesis, Medicine, Lung tumours, Ubiquitin Thiolesterase, Genetics & Genomics, Research Article, Human, Squamous cell lung carcinoma, Model organisms, QH301-705.5, Science, Chemical biology, USP28, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, squamous cell lung cancer, Biochemistry and Chemical Biology, medicine, Ubiquitin specific protease, Animals, Humans, Neoplasms, Squamous Cell, Survival rate, 030304 developmental biology, Lung, General Immunology and Microbiology, Tumour Biology, Disease Models, Animal, Cancer research, Carcinogenesis, Gene Deletion, Transcription Factors |
| الوصف: | Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient’s 5-year survival rate is less than 5%. The ubiquitin-specific protease 28 (USP28) has been implicated in tumourigenesis through its stabilization of the oncoproteins c-MYC, c-JUN, and Δp63. Here, we show that genetic inactivation of Usp28-induced regression of established murine LSCC lung tumours. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-MYC, c-JUN, and Δp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumours and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma. |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::beb8f4f7baf6b379b1145b3efa1b3fa6 https://elifesciences.org/articles/71596 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....beb8f4f7baf6b379b1145b3efa1b3fa6 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |