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The crucial p53-dependent oncogenic role of JAB1 in osteosarcoma in vivo

Oncogene volume 39, pages 4581–4591 (2020)Cite this article

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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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Fig. 1: The downregulation of JAB1 inhibits 143B and U2OS osteosarcoma cell growth in vitro.
Fig. 2: The RNA-seq analysis of JAB1-depleted 143B human OS cells.
Fig. 3: The Gene set enrichment analysis identifies altered oncogenic pathways upon JAB1-knockdown in 143B OS cells.
Fig. 4: JAB1 is overexpressed in human OS biopsies, and JAB1-knockdown increases apoptosis and alters multiple major signal transduction pathways in OS cells.
Fig. 5: The osteoblast-specific overexpression of Jab1 results in accelerated, spontaneous, and p53-dependent OS formation in mice.
Fig. 6: The characterization of spontaneous OS tumors in Col1a1-Jab1; p53+/− mice.
Fig. 7: JAB1 is a potential therapeutic target in osteosarcoma.

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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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Authors and Affiliations

  1. Department of Orthopaedics, Case Western Reserve University, Cleveland, OH, USA

    William E. Samsa, Murali K. Mamidi, Lindsay A. Bashur & Guang Zhou

  2. Case Comprehensive Cancer Center, Cleveland, OH, USA

    William E. Samsa, Murali K. Mamidi, Alexander Miron, David Danielpour & Guang Zhou

  3. Department of Pathology, Cleveland, OH, USA

    Robin Elliott

  4. Department of Genetics and Genome Sciences, Cleveland, OH, USA

    Alexander Miron & Guang Zhou

  5. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Yuqing Chen & Brendan Lee

  6. Indiana University School of Medicine, Indianapolis, IN, USA

    Edward M. Greenfield

  7. Case Comprehensive Cancer Center, Institute for Computational Biology, Cleveland, OH, USA

    Ricky Chan

  8. Division of General Medical Sciences, Cleveland, OH, USA

    David Danielpour

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Contributions

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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Correspondence to Guang Zhou.

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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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