The Crucial p53-Dependent Oncogenic Role of JAB1 in Osteosarcoma in vivo
dc.contributor.author | Samsa, William E. | |
dc.contributor.author | Mamidi, Murali K. | |
dc.contributor.author | Bashur, Lindsay A. | |
dc.contributor.author | Elliott, Robin | |
dc.contributor.author | Miron, Alexander | |
dc.contributor.author | Chen, Yuqing | |
dc.contributor.author | Lee, Brendan | |
dc.contributor.author | Greenfield, Edward M. | |
dc.contributor.author | Chan, Ricky | |
dc.contributor.author | Danielpour, David | |
dc.contributor.author | Zhou, Guang | |
dc.contributor.department | Orthopaedic Surgery, School of Medicine | en_US |
dc.date.accessioned | 2021-12-06T19:13:50Z | |
dc.date.available | 2021-12-06T19:13:50Z | |
dc.date.issued | 2020-06 | |
dc.description.abstract | Osteosarcoma (OS) is the most common primary bone cancer and ranks amongst the leading causes of cancer mortality in young adults. Jun activation domain binding protein 1 (JAB1) is overexpressed in many cancers and has recently emerged as a novel target for cancer treatment. However, the role of JAB1 in osteosarcoma was virtually unknown. In this study, we demonstrate that JAB1-knockdown in malignant osteosarcoma cell lines significantly reduced their oncogenic properties, including proliferation, colony formation, and motility. We also performed RNA-sequencing analysis in JAB1-knockdown OS cells and identified 4110 genes that are significantly differentially expressed. This demonstrated for the first time that JAB1 regulates a large and specific transcriptome in cancer. We also found that JAB1 is overexpressed in human OS and correlates with a poor prognosis. Moreover, we generated a novel mouse model that overexpresses Jab1 specifically in osteoblasts upon a TP53 heterozygous sensitizing background. Interestingly, by 13 months of age, a significant proportion of these mice spontaneously developed conventional OS. Finally, we demonstrate that a novel, highly specific small molecule inhibitor of JAB1, CSN5i-3, reduces osteosarcoma cell viability and has specific effects on the ubiquitin-proteasome system in OS. Thus, we show for the first time that the overexpression of JAB1 in vivo can result in accelerated spontaneous tumor formation in a p53-dependent manner. In summary, JAB1 might be a unique target for the treatment of osteosarcoma and other cancers. | en_US |
dc.eprint.version | Author's manuscript | en_US |
dc.identifier.citation | Samsa, W. E., Mamidi, M. K., Bashur, L. A., Elliott, R., Miron, A., Chen, Y., Lee, B., Greenfield, E. M., Chan, R., Danielpour, D., & Zhou, G. (2020). The Crucial p53-Dependent Oncogenic Role of JAB1 in Osteosarcoma in vivo. Oncogene, 39(23), 4581–4591. https://doi.org/10.1038/s41388-020-1320-6 | en_US |
dc.identifier.issn | 0950-9232 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/27131 | |
dc.language.iso | en_US | en_US |
dc.publisher | Nature | en_US |
dc.relation.isversionof | 10.1038/s41388-020-1320-6 | en_US |
dc.relation.journal | Oncogene | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | PMC | en_US |
dc.subject | Osteosarcoma (OS) | en_US |
dc.subject | Jun activation domain binding protein 1 (JAB1) | en_US |
dc.subject | primary bone cancer | en_US |
dc.title | The Crucial p53-Dependent Oncogenic Role of JAB1 in Osteosarcoma in vivo | en_US |
dc.type | Article | en_US |