Hsp90α Mediates BMI1 Expression in Breast Cancer Stem/Progenitor Cells through Facilitating Nuclear Translocation of c-Myc and EZH2
by
Yueh-Chun Lee 1,2,†, Wen-Wei Chang 3,4,†
, Yi-Ying Chen 3, Yu-Hung Tsai 3, Ying-Hsiang Chou 1,5, Hsien-Chun Tseng 1,6, Hsin-Lin Chen 1, Chun-Chieh Wu 1, Ju Chang-Chien 3,7, Hsueh-Te Lee 8, Huei-Fan Yang 1,9 and Bing-Yen Wang 10,11,12,13,*
Yueh-Chun Lee 1,2,†, Wen-Wei Chang 3,4,†, Yi-Ying Chen 3, Yu-Hung Tsai 3, Ying-Hsiang Chou 1,5, Hsien-Chun Tseng 1,6, Hsin-Lin Chen 1, Chun-Chieh Wu 1, Ju Chang-Chien 3,7, Hsueh-Te Lee 8, Huei-Fan Yang 1,9 and Bing-Yen Wang 10,11,12,13,*
1
Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
2
Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
3
School of Biomedical Sciences, Chung Shan Medical University, Taichung 40201, Taiwan
4
Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
5
Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung 40201, Taiwan
6
School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
7
Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung 40201, Taiwan
8
Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming University, Taipei 11529, Taiwan
9
Department of Nursing, Chung shan Medical University Hospital, Taichung 40201, Taiwan
10
Division of Thoracic Surgery, Department of Surgery, Changhua Christian Hospital, Changhua City 50006, Taiwan
11
School of Medicine, Chung Shan Medical University, 40201 Taichung, Taiwan
12
Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung 40201, Taiwan
13
School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
*
Author to whom correspondence should be addressed.
†
These authors contribute equally to this work.
Int. J. Mol. Sci. 2017, 18(9), 1986; https://doi.org/10.3390/ijms18091986
Received: 21 August 2017 / Revised: 13 September 2017 / Accepted: 14 September 2017 / Published: 15 September 2017
(This article belongs to the Special Issue Molecular Chaperones)
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.
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Keywords:
Hsp90α; BMI1; breast cancer stem cells; EZH2; c-Myc; nuclear translocation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
MDPI and ACS Style
Lee, Y.-C.; Chang, W.-W.; Chen, Y.-Y.; Tsai, Y.-H.; Chou, Y.-H.; Tseng, H.-C.; Chen, H.-L.; Wu, C.-C.; Chang-Chien, J.; Lee, H.-T.; Yang, H.-F.; Wang, B.-Y. Hsp90α Mediates BMI1 Expression in Breast Cancer Stem/Progenitor Cells through Facilitating Nuclear Translocation of c-Myc and EZH2. Int. J. Mol. Sci. 2017, 18, 1986.
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