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

Jichuan Wang, Osama Aldahamsheh, Alexander Ferrena, Hasibagan Borjihan, Amit Singla, Simon Yaguare, Swapnil Singh, Valentina Viscarret, Janet Tingling, Xiaolin Zi, Yungtai Lo, Richard Gorlick, Deyou Zheng, Edward L. Schwartz, Hongling Zhao, Rui Yang, David S. Geller, Bang H. Hoang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)90-104
Number of pages15
JournalAnnals of the New York Academy of Sciences
Volume1490
Issue number1
DOIs
StatePublished - Feb 18 2021

Keywords

  • SCF inhibitors
  • accumulation
  • osteosarcoma
  • p27
  • phosphorylation
  • transgenic mouse

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Fingerprint

Dive into the research topics of 'The interaction of SKP2 with p27 enhances the progression and stemness of osteosarcoma'. Together they form a unique fingerprint.

Cite this