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.
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Acknowledgements
The authors thank Teresa Pizzuto for her expert histology work. We also thank Dr Eva Altmann (Novartis) for the generous gift of CSN5i-3. This study was supported in part by the NCI R03 CA175874, the American Cancer Society Research Grant #119999-IRG-91-022-IRG, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health R01 AR068361 to GZ, and the T32 AR007505 to WES and LAB, as well as the Rally Foundation for Childhood Cancer Research and Open Hands Overflowing Hearts Fellowship to WES under award ID CON221575. This research was supported by the Cytometry and Imaging Microscopy Shared Resource of the Case Comprehensive Cancer Center (P30CA043703) and the Genomics Core Facility of the CWRU School of Medicine’s Genetics and Genome Sciences Department. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding
NCI R03 CA175874 to GZ, ACS #119999-IRG-91-022-18-IRG to GZ, NIAMS R01 AR068361 to GZ, NIAMS T32 AR7505-30 to WES and LAB, and the Rally Foundation for Childhood Cancer Research and Open Hands Overflowing Hearts Fellowship CON221575 to WES.
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Conception and design: WES, GZ. Development of methodology: WES, MKM, LAB, YC, BL, EG, DD, and GZ. Acquisition of data: WES, MKM, LAB, RE, AM, EG, and GZ. Analysis of data: WES, MKM, LAB, RE, RC, DD, and GZ. Writing of the paper: WES, MKM, DD, and GZ. Study supervision: WES, GZ.
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Samsa, W.E., Mamidi, M.K., Bashur, L.A. et al. The crucial p53-dependent oncogenic role of JAB1 in osteosarcoma in vivo. Oncogene 39, 4581–4591 (2020). https://doi.org/10.1038/s41388-020-1320-6
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DOI: https://doi.org/10.1038/s41388-020-1320-6
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