Cdh1-mediated Skp2 degradation by dioscin reprogrammes aerobic glycolysis and inhibits colorectal cancer cells growth
Cdh1-mediated Skp2 degradation by dioscin reprogrammes aerobic glycolysis and inhibits colorectal cancer cells growth
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Cdh1 介导的薯蓣皂苷降解 Skp2 重新编程有氧糖酵解并抑制结直肠癌细胞生长
DOI：
10.1016/j.ebiom.2019.11.031
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发表时间：
2019-12
期刊：
影响因子：
11.1
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Zhou L;Yu X;Li M;Gong G;Liu W;Li T;Zuo H;Li W;Gao F;Liu H
研究背景F-box蛋白S相蛋白相关蛋白2(Skp2)在包括结直肠癌在内的人类恶性肿瘤中呈高表达，且与预后不良相关。通过免疫印迹、免疫荧光、免疫组织化学染色、锚定依赖和非锚定生长实验、EDU掺入实验、泛素化分析、免疫共沉淀实验、基于CRISPR-Cas9的基因敲除实验和异种移植实验，检测Skp2在大肠癌组织和细胞株中的表达及薯蓣皂苷对糖酵解的抑制作用。Skp2基因敲除抑制了HK2和糖酵解，减少了结直肠癌细胞的体内外生长。我们筛选了88种商业上可用的天然产物，发现薯蓣皂苷，一种从几种植物中提取的天然类固醇皂苷，显著抑制了CRC细胞的糖酵解。薯蓣皂苷通过缩短Skp2的半衰期来降低Skp2的蛋白水平。进一步的研究表明，薯蓣皂苷减弱了S72上Skp2的磷酸化，促进了Skp2与CDH1的相互作用，最终促进了Skp2赖氨酸48(K48)连接的多泛素化和降解。耗尽CDH1可抑制薯蓣皂苷诱导的Skp2的减少，挽救HK2的表达，以及糖酵解。在小鼠异种移植模型中，薯蓣皂苷延缓了肿瘤的生长，促进了Skp2泛素化，并抑制了Skp2的表达。说明本研究表明，除了药物灭活Skp2外，增强泛素化依赖的Skp2周转是一种很有前途的癌症治疗方法。
BackgroundThe F-box protein S-phase kinase-associated protein 2 (Skp2) is overexpressed and correlated with poor prognosis in human malignancies, including colorectal cancer (CRC).MethodsA natural product library was used for natural compound screening through glycolysis analysis. The expression of Skp2 in CRCs and the inhibitory effect of dioscin on glycolysis were examined through methods of immunoblot, immunofluorescence, immunohistochemical staining, anchorage-dependent and -independent growth assays, EdU incorporation assay, ubiquitination analysis, co-immunoprecipitation assay, CRISPR-Cas9-based gene knockout, and xenograft experiment.FindingsWe demonstrated that Skp2 was highly expressed in CRC tissues and cell lines. Knockout of Skp2 inhibited HK2 and glycolysis and decreased CRC cell growthin vitroandin vivo. We screened 88 commercially available natural products and found that dioscin, a natural steroid saponin derived from several plants, significantly inhibited glycolysis in CRC cells. Dioscin decreased the protein level of Skp2 by shortening the half-life of Skp2. Further study showed that dioscin attenuated Skp2 phosphorylation on S72 and promoted the interaction between Skp2 and Cdh1, which eventually enhanced Skp2 lysine 48 (K48)-linked polyubiquitination and degradation. Depletion of Cdh1 impaired dioscin-induced Skp2 reduction, rescued HK2 expression, and glycolysis in CRC cells. Finally, dioscin delayed thein vivotumor growth, promoted Skp2 ubiquitination, and inhibited Skp2 expression in a mouse xenograft model.InterpretationThis study suggests that in addition to pharmacological inactivation of Skp2, enhancement of ubiquitination-dependent Skp2 turnover is a promising approach for cancer treatment.
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影响因子：
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作者：
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影响因子：
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