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

Yu-Min Huang,Shiow-Lin Pan,Chia-Hsiung Cheng,Ding-Yen Lin,Pei-Ming Yang,Kuen-Haur Lee

doi:10.3390/biom9110688

Abstract

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.

Highlights

Human high-mobility group A2 (HMGA2) is an architectural transcription factor with no transcriptional function
To discover a new inhibitor of HMGA2, we analyzed two Gene Expression Omnibus (GEO) datasets deposited into the National Center for Biotechnology Information (NCBI) (Figure 1)
The gene expression profiles from HMGA2 overexpression of human colorectal cancer (CRC) DLD-1 cells were derived from the GEO dataset (GSE136544) [27]

Summary

Introduction

Human high-mobility group A2 (HMGA2) is an architectural transcription factor with no transcriptional function. HMGA2 can regulate gene expression, DNA replication, and chromosome repair by binding to the minor groove of DNA through AT-hook motifs [1]. HMGA2 influences a variety of biological processes, including the cell cycle process, apoptosis, the DNA damage repair process, and epithelial–mesenchymal transition [2]. HMGA protein overexpression is associated with neoplastic transformation [3]. The HMGA2 protein is overexpressed in various types of cancer, including lung cancer [4], ovarian cancer [5], breast cancer [6], oral squamous cell carcinoma [7], pancreatic cancer [8], and colorectal cancer [9]. The accumulated evidence suggests that high expression of HMGA2 is related to tumor progression, poor prognosis, and a poor response to therapy [10,11]

Methods

Results

Conclusion