USP28 and USP25 are downregulated by Vismodegib in vitro and in colorectal cancer cell lines
文献类型：期刊论文
| 作者 | Wang, Hui2,3; Meng, Qian1; Ding, Yiluan2; Xiong, Muya1,3; Zhu, Mengying2,3; Yang, Yuanyuan2,3; Su, Haixia1,3; Gu, Lei1,3; Xu, Yechun1,3 ; Shi, Li2
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| 刊名 | FEBS JOURNAL
 |
| 出版日期 | 2020-07-20 |
| 页码 | 18 |
| 关键词 | colorectal cancer HDX-MS inhibitor USP25 USP28 Vismodegib |
| ISSN号 | 1742-464X |
| DOI | 10.1111/febs.15461 |
| 通讯作者 | Shi, Li(shili@simm.ac.cn) ; Zhou, Hu(zhouhu@simm.ac.cn) ; Zhang, Naixia(nxzhang@simm.ac.cn) |
| 英文摘要 | Deubiquitinase USP28 plays a crucial role in tumorigenesis by enhancing the stabilities of multiple cancer-related proteins including c-Myc, Notch1, and LSD1, and has become an attractive target for anticancer drug development. However, to date, only a few of USP28-targeted active compounds have been developed, and the active compound-binding pocket in USP28 has not been experimentally revealed yet. In this study, bioassay-based high-throughput screening was applied to discover USP28-targeted inhibitors from the commercially available drug library. Vismodegib, an inhibitor of Hedgehog signaling pathway and FDA-approved drug for the treatment of basal cell carcinoma, was found to exhibit inhibition activity against USP28 (IC50: 4.41 +/- 1.08 mu m). Multiple biophysical and biochemical techniques including NMR, ITC, thermal shift assay, HDX-MS, and site-directed mutagenesis analysis were then used to characterize the interaction between Vismodegib and USP28. The binding pocket in USP28 for Vismodegib, which is mainly composed of two helical structures spanning D255-N278 and N286-Y293, was revealed. According to the possible binding pose generated by HDX-MS data-defined molecular docking, the binding cavity occupied by Vismodegib in USP28 aligns well with one of the reported-binding pockets in USP7 for its inhibitors. Furthermore, cellular assays were conducted to confirm that Vismodegib could interact with the evolutionarily related deubiquitinases USP28 and USP25 and downregulate the levels of the two enzymes' substrate proteins c-Myc, Notch1, and Tankyrase-1/2. |
| WOS关键词 | DEUBIQUITINASE INHIBITION ; INTESTINAL HOMEOSTASIS ; SIGNAL-TRANSDUCTION ; CENTROSOME LOSS ; UBIQUITIN ; P53 ; STABILIZES ; ACTIVATION ; PROTEIN ; ENZYME |
| 资助项目 | National Natural Science Foundation of China[21977105] ; National Natural Science Foundation of China[21778061] ; National Science & Technology Major Project 'Key New Drug Creation and Manufacturing Program' of China[2018ZX09711002] |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000550433200001 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/292201]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Shi, Li; Zhou, Hu; Zhang, Naixia |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Hui,Meng, Qian,Ding, Yiluan,et al. USP28 and USP25 are downregulated by Vismodegib in vitro and in colorectal cancer cell lines[J]. FEBS JOURNAL,2020:18. |
| APA | Wang, Hui.,Meng, Qian.,Ding, Yiluan.,Xiong, Muya.,Zhu, Mengying.,...&Zhang, Naixia.(2020).USP28 and USP25 are downregulated by Vismodegib in vitro and in colorectal cancer cell lines.FEBS JOURNAL,18. |
| MLA | Wang, Hui,et al."USP28 and USP25 are downregulated by Vismodegib in vitro and in colorectal cancer cell lines".FEBS JOURNAL (2020):18. |
入库方式： OAI收割
来源：上海药物研究所
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