Abstract 3117: Overexpression of the stress transcription co-activator LEDGF/p75 contributes to the upregulation of the stress protective genes HSP27, ERp57 and CYGB in prostate cancer.

Abstract

Abstract Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer related death in men in the US. PCa tumor aggressiveness, response to treatment, and mortality are worst in African-American men, compared to other ethnic groups, thus presenting a major health disparity. Our group reported previously that lens epithelium derived growth factor p75 (LEDGF/p75), a stress survival transcription coactivator, has elevated expression in PCa cells and tissues and promotes resistance to cell death induced by oxidative stress and chemotherapy. This is likely due to its ability to transactivate promoter regions of stress and antioxidant genes such as peroxiredoxin 6 (Prdx6) and heat shock protein 27 (HSP27). We hypothesized that high expression of LEDGF/p75 in prostate tumor cells and tissues contributes to the elevated expression of its putative target genes, some of which were identified in previous studies by our group and others. These include genes associated with stress protection and chemotherapy resistance such as HSP27, endoplasmic reticulum protein 57 (ERp57), and cytoglobin (CYGB). To test this hypothesis we performed an expression analysis of LEDGF/p75, HSP27, ERp57 and CYGB proteins in human PCa cell lines using immunoblotting, and in prostate tumor tissues using immunohistochemistry on tumor tissue microarrays (TMAs). PCa cell lines included stable PC3 clones overexpressing LEDGF/p75, as well as docetaxel (DTX) resistant PC3-DR and DU145-DR cells overexpressing this protein, with their corresponding parental DTX sensitive cell lines. The TMAs contained tissue specimens corresponding to prostate tumor, hyperplasia, normal-adjacent, and disease-free normal prostate tissues. Correlations between the expression of LEDGF/p75 and HSP27 or ERp57 or CYGB in cell lines as well as in tumors and normal tissues was determined. Our results indicated that overexpression of LEDGF/p75 in PC3 stable clones and in DTX resistant PCa cells was associated with increased protein expression of HSP27, ERp57 and CYGB. Statistically significant correlation was also observed between the protein levels of LEDGF/p75 and HSPp27 or ERp57 or CYGB in the TMAs. Luciferase-based transcription reporter assays confirmed that the promoter regions of HSP27 and ERp57 are activated by LEDGF/p75 in PCa cells. Chromatin immunoprecipitation assays also demonstrated binding of LEDGF/p75 to HSP27 promoter in PCa cells. Additional promoter activation studies are in progress to demonstrate that LEDGF/p75 transcriptionally regulates ERp57 and CYGB genes. These results enhance our understanding of the contribution of LEDGF/p75 overexpression to the activation of stress protective genes and its implications for chemotherapy resistance in metastatic PCa. Citation Format: Anamika Basu, Christina Cajigas, Benanette Medina, Heather Rojas, Hiya Banerjee, Melanie Mediavilla-Varela, Laisum Leoh, Carlos Casiano. Overexpression of the stress transcription co-activator LEDGF/p75 contributes to the upregulation of the stress protective genes HSP27, ERp57 and CYGB in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3117. doi:10.1158/1538-7445.AM2013-3117