Accession Number:

ADA614029

Title:

Extracellular Hsp90 as a Novel Epigenetic of EMT and Metastatic Risk in Prostate Cancer

Descriptive Note:

Annual rept. 20 Sep 2013-19 Sep 2014

Corporate Author:

MEDICAL UNIV OF SOUTH CAROLINA CHARLESTON

Personal Author(s):

Report Date:

2014-10-01

Pagination or Media Count:

15.0

Abstract:

In general, the role of eHsp90 in tumor progression has not been well characterized. Our work provides novel mechanistic insights into the EMT-promoting activity of eHsp90. Our findings demonstrate that eHsp90-dependent upregulation of EZH2 is important not only for E-cadherin repression, but also for upregulated expression of several EMT effectors, including Snail, also a known repressor of E-cadherin. Blockade of eHsp90 via NPGA restored E-cadherin expression in several aggressive prostate cancer cell lines, indicating that these cell types are inherently reliant upon eHsp90 action for at least a subset of their malignant properties. Our findings validate the ability of eHsp90 to exert dynamic epigenetic reprogramming at select target genes to enforce EMT events. Our collective findings indicate that HDAC12, Snail, and EZH2 cooperate to modulate E-cadherin expression. From a clinical standpoint, it is imperative to understand these molecular relationships towards the goal of dampening EMT activation. While inhibition of EZH2 and HDAC activity may be suitable for restoration of eHsp90-repressed targets i.e. E-cadherin, it is also essential to clarify their effects upon chromatin remodeling at sites of eHsp90-activated targets such as Snail and Zeb.

Subject Categories:

  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE