The inhibitory effect of compound ChlA-F on human bladder cancer cell invasion can be attributed to its blockage of SOX2 protein
Hua, Xiaohui1; Huang, Maowen1; Deng, Xu2; Xu, Jiheng3; Luo, Yisi1; Xie, Qipeng1; Xu, Jiawei3; Tian, Zhongxian3; Li, Jingxia3; Zhu, Junlan3; Huang, Chao3; Zhao, Qin-shi2; Huang, Haishan1; Huang, Chuanshu3
Corresponding AuthorZhao, Qin-shi(qinshizhao@mail.kib.ac.cn) ; Huang, Haishan(haishan_333@163.com) ; Huang, Chuanshu(Chuanshu.huang@nyulangone.org)
2020-02-01
Source PublicationCELL DEATH AND DIFFERENTIATION
ISSN1350-9047
Volume27Issue:2Pages:632-645
AbstractSex-determining region Y-box 2 (SOX2), a well-known stemness biomarker, is highly expressed in a variety of cancers, including human highly invasive bladder cancer (BC). However, the role of SOX2 may vary in different kinds of malignancy. In the present study, we discovered that ChlA-F, a novel conformation derivative of isolate Cheliensisin A (Chel A), remarkably inhibits the invasive ability of human invasive BC cells through downregulation of SOX2 protein expression. We found that ChlA-F treatment dramatically decreases SOX2 protein expression in human high-grade invasive BC cells. Ectopic expression of SOX2 reversed ChlA-F inhibition of cell invasion ability in human bladder cancer cells, suggesting that SOX2 is a major target of ChlA-F during its inhibition of human BC invasion. Mechanistic studies revealed that ChlA-F downregulates SOX2 at both the protein degradation and protein translation levels. Further studies revealed that ChlA-F treatment induces HuR protein expression and that the increased HuR interacts with USP8 mRNA, resulting in elevation of USP8 mRNA stability and protein expression. Elevated USP8 subsequently acts as an E3 ligase to promote SOX2 ubiquitination and protein degradation. We also found that ChlA-F treatment substantially increases c-Jun phosphorylation at Ser63 and Ser73, initiating miR-200c transcription. The increased miR-200c directly binds to the 3 '-UTR of SOX2 mRNA to suppress SOX2 protein translation. These results present novel mechanistic insight into understanding SOX2 inhibition upon ChlA-F treatment and provide important information for further exploration of ChlA-F as a new therapeutic compound for the treatment of highly invasive/metastatic human BC patients.
DOI10.1038/s41418-019-0377-7
Indexed BySCI ; SCI
Language英语
WOS IDWOS:000510936500016
Citation statistics
Document Type期刊论文
Identifierhttp://ir.kib.ac.cn/handle/151853/70862
Collection植物化学与西部植物资源持续利用国家重点实验室
Corresponding AuthorZhao, Qin-shi; Huang, Haishan; Huang, Chuanshu
Affiliation1.Wenzhou Med Univ, Zhejiang Prov Key Lab Technol & Applicat Model Or, Key Lab Lab Med, Minist Educ China,Sch Lab Med & Life Sci, Wenzhou, Zhejiang, Peoples R China
2.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650204, Yunnan, Peoples R China
3.NYU, Sch Med, Dept Environm Med, 341 East 25th St, New York, NY 10010 USA
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Hua, Xiaohui,Huang, Maowen,Deng, Xu,et al. The inhibitory effect of compound ChlA-F on human bladder cancer cell invasion can be attributed to its blockage of SOX2 protein[J]. CELL DEATH AND DIFFERENTIATION,2020,27(2):632-645.
APA Hua, Xiaohui.,Huang, Maowen.,Deng, Xu.,Xu, Jiheng.,Luo, Yisi.,...&Huang, Chuanshu.(2020).The inhibitory effect of compound ChlA-F on human bladder cancer cell invasion can be attributed to its blockage of SOX2 protein.CELL DEATH AND DIFFERENTIATION,27(2),632-645.
MLA Hua, Xiaohui,et al."The inhibitory effect of compound ChlA-F on human bladder cancer cell invasion can be attributed to its blockage of SOX2 protein".CELL DEATH AND DIFFERENTIATION 27.2(2020):632-645.
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