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Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer

by Yu-Min Huang 1,2, Chia-Hsiung Cheng 3, Shiow-Lin Pan 4,5,6,†, Pei-Ming Yang 5,6,†, Ding-Yen Lin 5,7 and Kuen-Haur Lee 5,6,8,9,*
1
Department of Surgery, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
2
Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 11031, Taiwan
3
Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
4
Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
5
Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
6
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
7
Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 003107, Taiwan
8
TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
9
Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Biomolecules 2019, 9(11), 688; https://doi.org/10.3390/biom9110688
Received: 4 October 2019 / Revised: 30 October 2019 / Accepted: 31 October 2019 / Published: 2 November 2019
Human high-mobility group A2 (HMGA2) encodes for a non-histone chromatin protein which influences a variety of biological processes, including the cell cycle process, apoptosis, the DNA damage repair process, and epithelial–mesenchymal transition. The accumulated evidence suggests that high expression of HMGA2 is related to tumor progression, poor prognosis, and a poor response to therapy. Thus, HMGA2 is an important molecular target for many types of malignancies. Our recent studies revealed the positive connections between heat shock protein 90 (Hsp90) and HMGA2 and that the Hsp90 inhibitor has therapeutic potential to inhibit HMGA2-triggered tumorigenesis. However, 43% of patients suffered visual disturbances in a phase I trial of the second-generation Hsp90 inhibitor, NVP-AUY922. To identify a specific inhibitor to target HMGA2, the Gene Expression Omnibus (GEO) database and the Library of Integrated Network-based Cellular Signatures (LINCS) L1000platform were both analyzed. We identified the approved small-molecule antifungal agent ciclopirox (CPX) as a novel potential inhibitor of HMGA2. In addition, CPX induces cytotoxicity of colorectal cancer (CRC) cells by induction of cell cycle arrest and apoptosis in vitro and in vivo through direct interaction with the AT-hook motif (a small DNA-binding protein motif) of HMGA2. In conclusion, this study is the first to report that CPX is a novel potential inhibitor of HMGA2 using a drug-repurposing approach, which can provide a potential therapeutic intervention in CRC patients. View Full-Text
Keywords: HMGA2; CPX; gene signature; LINCS L1000 HMGA2; CPX; gene signature; LINCS L1000
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Huang, Y.-M.; Cheng, C.-H.; Pan, S.-L.; Yang, P.-M.; Lin, D.-Y.; Lee, K.-H. Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer. Biomolecules 2019, 9, 688.

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