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Mol Pharmacol. 2019 Aug;96(2):168-179. doi: 10.1124/mol.119.116137. Epub 2019 Jun 7.

Inhibition of Heat Shock Protein 90 suppresses TWIST1 Transcription.

Author information

1
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut (K.Y.C., M.K., F.G., S.C., T.M.P.H., Y.Y.-H.); The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (M.K.); Ronald Reagan UCLA Medical Center, University of California Los Angeles, Santa Monica, California (D.U., B.M.S.); Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China (H.L.); Department of Biology and Environmental Science, University of New Haven, West Haven, Connecticut (O.M., N.P., C.-H.T.); and Yale Cancer Center, New Haven, Connecticut (Y.Y.-H.).
2
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut (K.Y.C., M.K., F.G., S.C., T.M.P.H., Y.Y.-H.); The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (M.K.); Ronald Reagan UCLA Medical Center, University of California Los Angeles, Santa Monica, California (D.U., B.M.S.); Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China (H.L.); Department of Biology and Environmental Science, University of New Haven, West Haven, Connecticut (O.M., N.P., C.-H.T.); and Yale Cancer Center, New Haven, Connecticut (Y.Y.-H.) yang.yang@yale.edu.

Abstract

Molecular chaperone heat shock protein 90 (HSP90) is involved in oncogenic signaling pathways including epithelial-mesenchymal transition (EMT), a key process in tumor initiation, progression, metastasis, and chemoresistance. The molecular mechanisms underlying the involvement of HSP90 in EMT are still under investigation. In this study, we identified a previously unrecognized role of HSP90 in cooperating with signal transducer and activator of transcription 3 (STAT3) to regulate TWIST1 transcription in cancer cells. The HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin suppressed TWIST1 mRNA expression and promoter activity in epithelial ovarian cancer, renal clear cell cancer, and nasopharyngeal cancer cell lines. The interactions between HSP90 and transcription factors were visualized in cancer cell lines and tumor tissues using proximity ligation assays. Our findings reveal that HSP90 promotes the binding of STAT3 to the TWIST1 promoter, leading to the transcription of TWIST1. The inhibition of HSP90 downregulates STAT3 activity and TWIST1 transcription, thereby suppressing EMT and potentially inhibiting tumor progression, metastasis, and chemoresistance in different types of cancers. SIGNIFICANCE STATEMENT: Our study provides new evidence that HSP90 promotes EMT through enhancing TWIST1 transcription, which can be suppressed by HSP90 inhibitors. The HSP90 inhibitor inhibits EMT, thus potentially slowing down tumor growth, invasion, dissemination, metastasis, and drug resistance. These findings will hopefully pave the way for new therapeutic opportunities to target EMT and metastasis using HSP90 inhibitors.

PMID:
31175180
DOI:
10.1124/mol.119.116137

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