The interaction of SKP2 with p27 enhances the progression and stemness of osteosarcoma

• Main Authors: Aldahamsheh, O. (Author), Borjihan, H. (Author), Ferrena, A. (Author), Geller, D.S (Author), Gorlick, R. (Author), Hoang, B.H (Author), Lo, Y. (Author), Schwartz, E.L (Author), Singh, S. (Author), Singla, A. (Author), Tingling, J. (Author), Viscarret, V. (Author), Wang, J. (Author), Yaguare, S. (Author), Yang, R. (Author), Zhao, H. (Author), Zheng, D. (Author), Zi, X. (Author)
• Format: Article
• Language: English
• Published: John Wiley and Sons Inc 2021
• Subjects: accumulation; alkaline phosphatase; animal; animal experiment; animal model; animal tissue; Animals; antiproliferative activity; apoptosis; Article; C57BL mouse; cancer growth; cancer stem cell; carcinogenesis; Carcinogenesis; caspase 3; CD133 antigen; cell culture; cell cycle arrest; cell proliferation; Cells, Cultured; controlled study; cyclin dependent kinase inhibitor 1B; Cyclin-Dependent Kinase Inhibitor p27; cycloheximide; gene expression; gene expression regulation; Gene Expression Regulation, Neoplastic; gene knockout; gene loss; gene mutation; genetically engineered mouse strain; genetics; human; human cell; Humans; immunofluorescence; immunohistochemistry; in vitro study; in vivo study; jaw tumor; knockout mouse; limb tumor; lung metastasis; lung nodule; male; messenger RNA; metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; missense mutation; mouse; nonhuman; osteocalcin; osteosarcoma; Osteosarcoma; overall survival; oxidative phosphorylation; p27; pathology; penetrance; pevonedistat; phosphorylation; primary culture; primary tumor; protein depletion; protein p27; protein p53; protein phosphorylation; protein protein interaction; Rb1 protein, mouse; retinoblastoma binding protein; Retinoblastoma Binding Proteins; retinoblastoma protein; RNA sequencing; S phase kinase associated protein; S phase kinase associated protein 2; SCFSKP2 inhibitors; S-Phase Kinase-Associated Proteins; stem cell factor receptor; transcription regulation; transgenic mouse; Trp53 protein, mouse; Tumor Suppressor Protein p53; tumor volume; Western blotting
• Online Access: View Fulltext in Publisher

 Osteosarcoma is a highly aggressive malignancy for which treatment has remained essentially unchanged for years. Our previous studies found that the F-box protein SKP2 is overexpressed in osteosarcoma, acting as a proto-oncogene; p27Kip1 (p27) is an inhibitor of cyclin-dependent kinases and a downstream substrate of SKP2-mediated ubiquitination. Overexpression of SKP2 and underexpression of p27 are common characteristics of cancer cells. The SCFSKP2 E3 ligase ubiquitinates Thr187-phosphorylated p27 for proteasome degradation, which can be abolished by a Thr187Ala knock-in (p27T187A KI) mutation. RB1 and TP53 are two major tumor suppressors commonly coinactivated in osteosarcoma. We generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which developed osteosarcoma with full penetrance. When p27T187A KI mice were crossed on to the DKO background, p27T187A protein was found to accumulate in osteosarcoma tumor tissues. Furthermore, p27T187A promoted apoptosis in DKO tumors, slowed disease progression, and significantly prolonged overall survival. RNA sequencing analysis also linked the SCFSKP2–p27T187A axis to potentially reduced cancer stemness. Given that RB1 and TP53 loss or coinactivation is common in human osteosarcoma, our study suggests that inhibiting the SKP2–p27 axis may represent a desirable therapeutic strategy for this cancer. © 2021 New York Academy of Sciences.