Abstract 1448: Dynamic chromatin modification by tumor secreted Hsp90 modulates EMT and tumor invasion

Abstract

Abstract Tumor metastasis is the main cause of prostate cancer lethality. Pathological reactivation of the developmental genetic program epithelial to mesenchymal (EMT) is associated with increased tumorigenesis and invasion, and is considered a primary culprit for tumor dissemination. Hallmarks of EMT include upregulation of the core transcription factors Zeb and Snail, concomitant with suppression of the junctional protein E-cadherin. Overexpression of the epigenetic repressor EZH2, a histone methyltransferase, is also implicated in EMT activation. Although these molecular events are well known to trend with cancer progression, a paucity of knowledge exists regarding identification of the clinically-relevant upstream triggers capable of setting these events into motion. We recently demonstrated that tumor secreted extracellular heat shock protein 90 (eHsp90) initiates EMT events in prostate cancer cells. Moreover, we reported the presence of surface Hsp90 in human prostatectomy specimens, an event highly correlated with elevated expression of a subset of EMT transcripts. The present study reveals novel mechanistic aspects of eHsp90 action. We define an epigenetic function for eHsp90 as a significant regulator of EZH2 expression and activity. This eHsp90-EZH2 axis was found to govern a majority of eHsp90's pro-EMT activity in vitro, and was essential for E-cadherin suppression and tumor invasion in vivo. Upon further investigation, it was revealed that eHsp90 sustained ERK activation. This eHsp90-ERK pathway was required for the increased expression of EZH2, as well as for its directed recruitment to the E-cadherin promoter. Moreover, eHsp90-ERK signaling augmented the epigenetic landscape of Zeb and Snail towards a profile permissive for transcriptional activation. Hence, our findings indicate that eHsp90-ERK signaling has profound effects upon key drivers of cancer progression via the concerted action of epigenetic modulation of EMT effectors and increased EZH2 expression. Collectively, these data support a model wherein tumor eHsp90 functions as an upstream rheostat for EZH2 expression and activity to orchestrate mesenchymal properties and coincident aggressive behavior. Importantly, our findings suggest that eHsp90 may be a clinically relevant instigator in the transition from localized to invasive disease. Citation Format: Krystal D. Nolan, Michael W. Hance, Omar E. Franco, Simon W. Hayward, Jennifer S. Isaacs. Dynamic chromatin modification by tumor secreted Hsp90 modulates EMT and tumor invasion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1448. doi:10.1158/1538-7445.AM2015-1448