Heat shock protein 90 is involved in the regulation of HMGA2-driven growth and epithelial-to-mesenchymal transition of colorectal cancer cells

Chun-Yu Kao; Pei-Ming Yang; Ming-Heng Wu; Chi-Chen Huang; Yi-Chao Lee; Kuen-Haur Lee

doi:10.7717/peerj.1683

Heat shock protein 90 is involved in the regulation of HMGA2-driven growth and epithelial-to-mesenchymal transition of colorectal cancer cells

PeerJ. 2016 Feb 11:4:e1683. doi: 10.7717/peerj.1683. eCollection 2016.

Authors

Chun-Yu Kao¹, Pei-Ming Yang^#², Ming-Heng Wu^#³, Chi-Chen Huang^#⁴, Yi-Chao Lee⁴, Kuen-Haur Lee²

Affiliations

¹ Department of Pediatric Surgery, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan.
² Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
³ Graduate Institute of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁴ Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.

^# Contributed equally.

Abstract

High Mobility Group AT-hook 2 (HMGA2) is a nonhistone chromatin-binding protein which acts as a transcriptional regulating factor involved in gene transcription. In particular, overexpression of HMGA2 has been demonstrated to associate with neoplastic transformation and tumor progression in Colorectal Cancer (CRC). Thus, HMGA2 is a potential therapeutic target in cancer therapy. Heat Shock Protein 90 (Hsp90) is a chaperone protein required for the stability and function for a number of proteins that promote the growth, mobility, and survival of cancer cells. Moreover, it has shown strong positive connections were observed between Hsp90 inhibitors and CRC, which indicated their potential for use in CRC treatment by using combination of data mining and experimental designs. However, little is known about the effect of Hsp90 inhibition on HMGA2 protein expression in CRC. In this study, we tested the hypothesis that Hsp90 may regulate HMGA2 expression and investigated the relationship between Hsp90 and HMGA2 signaling. The use of the second-generation Hsp90 inhibitor, NVP-AUY922, considerably knocked down HMGA2 expression, and the effects of Hsp90 and HMGA2 knockdown were similar. In addition, Hsp90 knockdown abrogates colocalization of Hsp90 and HMGA2 in CRC cells. Moreover, the suppression of HMGA2 protein expression in response to NVP-AUY922 treatment resulted in ubiquitination and subsequent proteasome-dependant degradation of HMGA2. Furthermore, RNAi-mediated silencing of HMGA2 reduced the survival of CRC cells and increased the sensitivity of these cells to chemotherapy. Finally, we found that the NVP-AUY922-dependent mitigation of HMGA2 signaling occurred also through indirect reactivation of the tumor suppressor microRNA (miRNA), let-7a, or the inhibition of ERK-regulated HMGA2 involved in regulating the growth of CRC cells. Collectively, our studies identify the crucial role for the Hsp90-HMGA2 interaction in maintaining CRC cell survival and migration. These findings have significant implications for inhibition HMGA2-dependent tumorigenesis by clinically available Hsp90 inhibitors.

Keywords: Colorectal cancer; HMGA2; Hsp90.

Grants and funding

This project was funded by the Ministry of Science and Technology of Taiwan (MOST 104-2320-B-038-006 to KHL), Taipei Medical University (TMU101-AE1-B19 and TMU104-AE2-I02-5 to KHL), Taipei Medical University-Shuang Ho Hospital (104TMU-SHH-10 to KHL) and the proposal of the Ministry of Health and Welfare (MOHW 104-TDU-B-212-124-001 to YY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.