The interaction of SKP2 with p27 enhances the progression and stemness of osteosarcoma. Issue 1 (16th February 2021)

• Record Type: Journal Article
• Authors: Wang, Jichuan; Aldahamsheh, Osama; Ferrena, Alexander; Borjihan, Hasibagan; Singla, Amit; Yaguare, Simon; Singh, Swapnil; Viscarret, Valentina; Tingling, Janet; Zi, Xiaolin; Lo, Yungtai; Gorlick, Richard; Zheng, Deyou; Schwartz, Edward L.; Zhao, Hongling; Yang, Rui; Geller, David S.; Hoang, Bang H.
• Other Names: Sun Hui B. guestEditor.
• Is Part Of: Annals of the New York Academy of Sciences. Volume 1490:Issue 1(2021)
• Page Start: 90
• Page End: 104
• Publication Date: 2021-02-16
• Subjects: p27 -- phosphorylation -- accumulation -- SCFSKP2 inhibitors -- transgenic mouse -- osteosarcoma; Medical sciences -- Periodicals; Medicine -- Periodicals; Science -- Periodicals; 610
• DOI: 10.1111/nyas.14578
• Languages: English
• ISSNs: 0077-8923

Abstract

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; p27 Kip1 (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 SCF SKP2 E3 ligase ubiquitinates Thr187‐phosphorylated p27 for proteasome degradation, which can be abolished by a Thr187Ala knock‐in (p27 T187A 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 p27 T187A KI mice were crossed on to the DKO background, p27 T187A protein was found to accumulate in osteosarcoma tumor tissues. Furthermore, p27 T187A promoted apoptosis in DKO tumors, slowed disease progression, and significantly prolonged overall survival. RNA sequencing analysis also linked the SCF SKP2 –p27 T187A 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. Abstract : The F‐box protein SKP2 is overexpressed in osteosarcoma, acting as a proto‐oncogene. p27 Kip1 (p27) is an inhibitor of cyclin‐dependent kinases and a downstream substrate of SKP2‐mediated ubiquitination. Using a genetically engineered mouse model (GEMM) with a knockout (DKO) of both Rb1 and Trp53 within cells of the osteoblastic lineage, we found that blocking the interaction of SKP2 and p27 promotes apoptosis and cell cycle arrest, and inhibits cancer stemness in osteosarcoma.