Inhibition of Heat Shock Protein 90 suppresses TWIST1 Transcription.

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.

• Authors: Kay Yi Chong, Min Kang, Francesca Garofalo, Daiki Ueno, Huamao Liang, Sarah Cady, Oluwagbemisola Madarikan, Nicholas Pitruzzello, Cheng-Hsiu Tsai, Tobias M P Hartwich, Brian M Shuch, Yang Yang-Hartwich
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 96 Issue 2 Pg. 168-179 (08 2019) ISSN: 1521-0111 [Electronic] United States
• PMID: 31175180 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Benzoquinones
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• Nuclear Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• TWIST1 protein, human
• Twist-Related Protein 1
• tanespimycin

Topics

• Benzoquinones (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Kidney Neoplasms (drug therapy, genetics, metabolism)
• Lactams, Macrocyclic (pharmacology)
• Nasopharyngeal Neoplasms (drug therapy, genetics, metabolism)
• Nuclear Proteins (genetics)
• Ovarian Neoplasms (drug therapy, genetics, metabolism)
• Phosphorylation (drug effects)
• Promoter Regions, Genetic (drug effects)
• STAT3 Transcription Factor (metabolism)
• Tissue Array Analysis
• Transcription, Genetic (drug effects)
• Twist-Related Protein 1 (genetics)