Hsp27 Regulates Epithelial Mesenchymal Transition, Metastasis, and Circulating Tumor Cells in Prostate Cancer

Abstract

Defining the mechanisms underlying metastatic progression of prostate cancer may lead to insights into how to decrease morbidity and mortality in this disease. An important determinant of metastasis is epithelial-to-mesenchymal transition (EMT), and the mechanisms that control the process of EMT in cancer cells are still emerging. Here, we report that the molecular chaperone Hsp27 (HSPB1) drives EMT in prostate cancer, whereas its attenuation reverses EMT and decreases cell migration, invasion, and matrix metalloproteinase activity. Mechanistically, silencing Hsp27 decreased IL-6-dependent STAT3 phosphorylation, nuclear translocation, and STAT3 binding to the Twist promoter, suggesting that Hsp27 is required for IL-6-mediated EMT via modulation of STAT3/Twist signaling. We observed a correlation between Hsp27 and Twist in patients with prostate cancer, with Hsp27 and Twist expression each elevated in high-grade prostate cancer tumors. Hsp27 inhibition by OGX-427, an antisense therapy currently in phase II trials, reduced tumor metastasis in a murine model of prostate cancer. More importantly, OGX-427 treatment decreased the number of circulating tumor cells in patients with metastatic castration-resistant prostate cancer in a phase I clinical trial. Overall, this study defines Hsp27 as a critical regulator of IL-6-dependent and IL-6-independent EMT, validating this chaperone as a therapeutic target to treat metastatic prostate cancer.

Small heat shock proteins in ageing and age-related diseases

“…EMT has been shown to play a fundamental role in metastasis. Intriguingly, HSPB1 mediates EMT, metastasis and circulating tumour cells in prostate cancer and breast cancer via modulation of STAT3/Twist signalling and nuclear factor-kappaB (NF-κB) respectively (Shiota et al 2013;Wei et al 2011). Endothelial to mesenchymal transition (EndMT) is another parameter known to be important for metastatic extravasation in brain endothelial cells and to promote invasiveness of infected endothelial cells, thus contributing to cancer progression (Gasperini et al 2012;Krizbai et al 2015).…”

“…OGX-427 is a secondgeneration antisense technology inhibitor that enables targeted downregulation of gene expression at the transcriptional level. It has been shown to potently reduce HSPB1 levels and in synergy with other cancer treatments to inhibit tumour growth, further validating these proteins as potential therapeutic targets for cancer treatment (Baylot et al 2011;Gleave and Monia 2005;Lamoureux et al 2014;Lelj-Garolla et al 2015;Shiota et al 2013). …”

Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer

“…Cell invasion assay was performed as described previously (Shiota et al 2013b). Briefly, cell invasion was performed using 8-mm pore matrigel invasion chambers (BD Biosciences).…”

Androgen receptor as a regulator of ZEB2 expression and its implications in epithelial-to-mesenchymal transition in prostate cancer

“…Several strides have been carried out to identify the factors contributing to EMT in PCa. Transforming growth factor beta (Zhu & Kyprianou 2010), nicotinamide adenine dinucleotide-dependent histone deacetylase or SIRT1 (Byles et al 2012), platelet-derived growth factor (Kong et al 2009), TMPRSS2/ERG (Leshem et al 2011), SNAI2 (SLUG) (Emadi Baygi et al 2010), DAB2IP (Xie et al 2010), Hsp27 (HSPB1) (Shiota et al 2013), and miRNAs (Ru et al 2012) have all been identified as EMT regulators in PCa. Interestingly, the majority of these factors mediate EMT via zinc finger E-box-binding protein (ZEB) family members, such as ZEB1 (dEF1 or AREB6) and ZEB2 (Smad-interacting protein 1 (SIP1)) (Gregory et al 2011).…”