The crucial p53-dependent oncogenic role of JAB1 in osteosarcoma in vivo.
Animals
Bone Neoplasms
/ genetics
COP9 Signalosome Complex
/ genetics
Carcinogenesis
/ genetics
Cell Cycle Checkpoints
/ genetics
Cell Line, Tumor
Cell Movement
/ genetics
Cell Proliferation
/ genetics
DNA Repair
/ genetics
Humans
Intracellular Signaling Peptides and Proteins
/ genetics
Mice
Osteosarcoma
/ genetics
Peptide Hydrolases
/ genetics
Tumor Suppressor Protein p53
/ metabolism
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
20
08
2019
accepted:
28
04
2020
revised:
23
04
2020
pubmed:
12
5
2020
medline:
26
11
2020
entrez:
12
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32390003
doi: 10.1038/s41388-020-1320-6
pii: 10.1038/s41388-020-1320-6
pmc: PMC7274902
mid: NIHMS1589186
doi:
Substances chimiques
Intracellular Signaling Peptides and Proteins
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Peptide Hydrolases
EC 3.4.-
COPS5 protein, human
EC 3.4.-.-
COP9 Signalosome Complex
EC 3.4.19.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4581-4591Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR068361
Pays : United States
Organisme : NCI NIH HHS
ID : R03 CA175874
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA043703
Pays : United States
Organisme : NIAMS NIH HHS
ID : T32 AR007505
Pays : United States
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