Hsp90α Mediates BMI1 Expression in Breast Cancer Stem/Progenitor Cells through Facilitating Nuclear Translocation of c-Myc and EZH2

International Journal of Molecular Sciences

Ying-Hsiang Chou¹  Chun-Chieh Wu¹  Hsin-Lin Chen¹  Hsien-Chun Tseng¹  Huei-Fan Yang¹  Yueh-Chun Lee¹  Bing-Yen Wang²  Hsueh-Te Lee³  Ju Chang-Chien⁴  Yi-Ying Chen⁴  Yu-Hung Tsai⁴  Wen-Wei Chang⁴ 

[1] Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan;Division of Thoracic Surgery, Department of Surgery, Changhua Christian Hospital, Changhua City 50006, Taiwan;Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming University, Taipei 11529, Taiwan;School of Biomedical Sciences, Chung Shan Medical University, Taichung 40201, Taiwan;

关键词: Hsp90α;    BMI1;    breast cancer stem cells;    EZH2;    c-Myc;    nuclear translocation;   

DOI  :  10.3390/ijms18091986

来源: DOAJ

【 摘 要 】

Heat shock protein 90 (Hsp90) is a molecular chaperone that facilitates the correct folding and functionality of its client protein. Numerous Hsp90-client proteins are involved in cancer development. Thus, Hsp90 inhibitors have potential applications as anti-cancer drugs. We previously discovered that Hsp90α expression increased in breast cancer stem cells (BCSCs), which can initiate tumorigenesis and metastasis and resist treatment. In the present study, we further demonstrated that 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), an inhibitor of Hsp90, could suppress the self-renewal of BCSCs by downregulating B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a polycomb family member with oncogenic activity in breast cancer. Through immunoprecipitation analysis, we found that BMI1 did not interact with Hsp90α and that the downregulation of BMI1 by 17-DMAG was mediated by the inhibition of c-Myc and enhancement of zeste homolog 2 (EZH2) expression. The transcriptional and BMI1 promoter-binding activities of c-Myc in BCSCs were inhibited by 17-DMAG treatment. The overexpression of EZH2 attenuated the inhibitory effect of 17-DMAG on BMI1 and c-Myc expression. Furthermore, Hsp90α could be co-immunoprecipitated with c-Myc and EZH2 and bind to the BMI1 promoter. Treatment with 17-DMAG decreased the nuclear expression of EZH2 and c-Myc but not that of Hsp90α. In conclusion, our data suggested that Hsp90α could positively regulate the self-renewal of BCSCs by facilitating the nuclear translocation of c-Myc and EZH2 to maintain BMI1 expression.

【 授权许可】

Unknown