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.
Highlights
High Mobility Group AT-hook (HMGA) nonhistone chromatin-binding proteins, including HMGA1 and HMGA2, are architectural nuclear factors involved in chromatin remodeling and gene transcription (Reeves & Nissen, 1990)
These results indicate that HMGA2 expression was specific and elevated in Colorectal Cancer (CRC) cells
Immunoprecipitation of HMGA2 followed by Western blot analysis with an anti-ubiquitin antibody detected significantly higher levels of ubiquitinated HMGA2 in the presence of the combination of MG132 and NVPAUY922, compared with either agent alone (Fig. 3F). These data suggest that downregulation of HMGA2 protein was a direct effect of Heat Shock Protein 90 (Hsp90) inhibition and indicate that Hsp90 is necessary for the stability of HMGA2
Summary
High Mobility Group AT-hook (HMGA) nonhistone chromatin-binding proteins, including HMGA1 (isoforms HMGA1a and HMGA1b) and HMGA2, are architectural nuclear factors involved in chromatin remodeling and gene transcription (Reeves & Nissen, 1990). HMGA2 is weakly expressed only in preadipocytic proliferating cells (Anand & Chada, 2000) and spermatocytes (Di Agostino et al, 2004). Several studies have reported that the association of HMGA2 overexpression with the transformation and metastatic progression of neoplastic cells suggests its causal role in carcinogenesis and tumor progression (Mahajan et al, 2010; Piscuoglio et al, 2012; Wang et al, 2011; Wend et al, 2013; Xu et al, 2004). The essential role of HMGA2 in cell proliferation and migration has been reported in various cancers (Malek et al, 2008; Sun et al, 2013; Xia et al, 2015; Yang et al, 2011). The HMGA2 protein is a promising biomarker for cancer detection as well as a potential molecular target in cancer therapy
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