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

• Published in: International journal of molecular sciences Vol. 18; no. 9; p. 1986
• Main Authors: Lee, Yueh-Chun, Chang, Wen-Wei, Chen, Yi-Ying, Tsai, Yu-Hung, Chou, Ying-Hsiang, Tseng, Hsien-Chun, Chen, Hsin-Lin, Wu, Chun-Chieh, Chang-Chien, Ju, Lee, Hsueh-Te, Yang, Huei-Fan, Wang, Bing-Yen
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 15.09.2017; MDPI
• Subjects: B-cell lymphoma; Benzoquinones - pharmacology; BMI1; Breast cancer; breast cancer stem cells; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; c-Myc; c-Myc protein; Cell Line, Tumor; Cell Self Renewal - genetics; Cell self-renewal; Cells (biology); Drug development; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; EZH2; Female; Gene Expression Regulation, Neoplastic; Heat shock proteins; Homology; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Hsp90α; Humans; Immunoprecipitation; Lactams, Macrocyclic - pharmacology; Metastases; Myc protein; Neoplastic Stem Cells - metabolism; nuclear translocation; Nuclear transport; Polycomb group proteins; Polycomb Repressive Complex 1 - genetics; Protein Binding; Protein folding; Protein Transport; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Stem cells; Transcription; Transcription, Genetic; Tumorigenesis; Hsp90α; breast cancer stem cells; BMI1; c-Myc; nuclear translocation; EZH2
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms18091986

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.