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The interaction of SKP2 with p27 enhances the progression and stemness of osteosarcoma
Annals of the New York Academy of Sciences ( IF 4.1 ) Pub Date : 2021-02-16 , DOI: 10.1111/nyas.14578 Jichuan Wang 1, 2 , Osama Aldahamsheh 1 , Alexander Ferrena 3 , Hasibagan Borjihan 1 , Amit Singla 1 , Simon Yaguare 1 , Swapnil Singh 1 , Valentina Viscarret 1 , Janet Tingling 1 , Xiaolin Zi 4 , Yungtai Lo 5 , Richard Gorlick 6 , Deyou Zheng 7, 8 , Edward L Schwartz 9 , Hongling Zhao 10 , Rui Yang 1 , David S Geller 1 , Bang H Hoang 1
Annals of the New York Academy of Sciences ( IF 4.1 ) Pub Date : 2021-02-16 , DOI: 10.1111/nyas.14578 Jichuan Wang 1, 2 , Osama Aldahamsheh 1 , Alexander Ferrena 3 , Hasibagan Borjihan 1 , Amit Singla 1 , Simon Yaguare 1 , Swapnil Singh 1 , Valentina Viscarret 1 , Janet Tingling 1 , Xiaolin Zi 4 , Yungtai Lo 5 , Richard Gorlick 6 , Deyou Zheng 7, 8 , Edward L Schwartz 9 , Hongling Zhao 10 , Rui Yang 1 , David S Geller 1 , Bang H Hoang 1
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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.
中文翻译：
SKP2 与 p27 的相互作用促进骨肉瘤的进展和干性
骨肉瘤是一种高度侵袭性的恶性肿瘤，其治疗方法多年来基本保持不变。我们前期的研究发现F-box蛋白SKP2在骨肉瘤中过度表达，作为原癌基因；p27 Kip1 (p27) 是细胞周期蛋白依赖性激酶的抑制剂，也是 SKP2 介导的泛素化的下游底物。SKP2的过度表达和p27的低表达是癌细胞的共同特征。SCF SKP2 E3 连接酶泛素化 Thr187 磷酸化的 p27 以进行蛋白酶体降解，这可以通过 Thr187Ala 敲入 (p27 T187A KI) 突变来消除。RB1和TP53是骨肉瘤中通常同时激活的两种主要肿瘤抑制因子。我们构建了成骨细胞谱系细胞内Rb1和Trp53双敲除 (DKO) 的小鼠模型，该模型产生了完全外显的骨肉瘤。当 p27 T187A KI 小鼠与 DKO 背景杂交时，发现p27 T187A蛋白在骨肉瘤肿瘤组织中积聚。此外，p27 T187A促进 DKO 肿瘤细胞凋亡，减缓疾病进展，并显着延长总体生存期。RNA 测序分析还将 SCF SKP2 –p27 T187A轴与潜在降低的癌症干性联系起来。鉴于RB1和TP53缺失或共同激活在人类骨肉瘤中很常见，我们的研究表明，抑制 SKP2-p27 轴可能是这种癌症的理想治疗策略。
更新日期：2021-04-19
中文翻译：
SKP2 与 p27 的相互作用促进骨肉瘤的进展和干性
骨肉瘤是一种高度侵袭性的恶性肿瘤，其治疗方法多年来基本保持不变。我们前期的研究发现F-box蛋白SKP2在骨肉瘤中过度表达，作为原癌基因；p27 Kip1 (p27) 是细胞周期蛋白依赖性激酶的抑制剂，也是 SKP2 介导的泛素化的下游底物。SKP2的过度表达和p27的低表达是癌细胞的共同特征。SCF SKP2 E3 连接酶泛素化 Thr187 磷酸化的 p27 以进行蛋白酶体降解，这可以通过 Thr187Ala 敲入 (p27 T187A KI) 突变来消除。RB1和TP53是骨肉瘤中通常同时激活的两种主要肿瘤抑制因子。我们构建了成骨细胞谱系细胞内Rb1和Trp53双敲除 (DKO) 的小鼠模型，该模型产生了完全外显的骨肉瘤。当 p27 T187A KI 小鼠与 DKO 背景杂交时，发现p27 T187A蛋白在骨肉瘤肿瘤组织中积聚。此外，p27 T187A促进 DKO 肿瘤细胞凋亡，减缓疾病进展，并显着延长总体生存期。RNA 测序分析还将 SCF SKP2 –p27 T187A轴与潜在降低的癌症干性联系起来。鉴于RB1和TP53缺失或共同激活在人类骨肉瘤中很常见，我们的研究表明，抑制 SKP2-p27 轴可能是这种癌症的理想治疗策略。
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