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

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 expressi...

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Autores principales: Huang, Yu-Min, Cheng, Chia-Hsiung, Pan, Shiow-Lin, Yang, Pei-Ming, Lin, Ding-Yen, Lee, Kuen-Haur
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920845/
https://www.ncbi.nlm.nih.gov/pubmed/31684108
http://dx.doi.org/10.3390/biom9110688
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author Huang, Yu-Min
Cheng, Chia-Hsiung
Pan, Shiow-Lin
Yang, Pei-Ming
Lin, Ding-Yen
Lee, Kuen-Haur
author_facet Huang, Yu-Min
Cheng, Chia-Hsiung
Pan, Shiow-Lin
Yang, Pei-Ming
Lin, Ding-Yen
Lee, Kuen-Haur
author_sort Huang, Yu-Min
collection PubMed
description 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.
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spelling pubmed-69208452019-12-24 Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer Huang, Yu-Min Cheng, Chia-Hsiung Pan, Shiow-Lin Yang, Pei-Ming Lin, Ding-Yen Lee, Kuen-Haur Biomolecules Article 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. MDPI 2019-11-02 /pmc/articles/PMC6920845/ /pubmed/31684108 http://dx.doi.org/10.3390/biom9110688 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huang, Yu-Min
Cheng, Chia-Hsiung
Pan, Shiow-Lin
Yang, Pei-Ming
Lin, Ding-Yen
Lee, Kuen-Haur
Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer
title Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer
title_full Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer
title_fullStr Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer
title_full_unstemmed Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer
title_short Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer
title_sort gene expression signature-based approach identifies antifungal drug ciclopirox as a novel inhibitor of hmga2 in colorectal cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920845/
https://www.ncbi.nlm.nih.gov/pubmed/31684108
http://dx.doi.org/10.3390/biom9110688
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