Abstract POSTER-BIOL-1344: Epigenetic regulation of SPARC in ovarian cancer

Abstract

Abstract Background: We have previously reported the tumor suppressor effect of Secreted protein acidic and rich in cysteine (SPARC) in ovarian cancer in vitro and in vivo. We reported that SPARC suppresses ovarian cancer cells interactions with the surrounding environmental cues within the peritoneal milieu. We also reported that the expression of SPARC was decreased in established ovarian cancer cell lines and micro-dissected ovarian cancer cells from advanced tumors consistent with hypermethylation of its promoter. However, the mechanisms of epigenetic regulation of SPARC in ovarian cancer (and other morbidities) are unraveled. Experimental Procedures: In silico analysis, human ovarian cancer tissue microarrays, a panel of established human ovarian cancer cell lines and in vitro ovarian cancer cell models were used. Genetic and pharmacologic manipulation of NFκB subunits and DNA methyl transferases (DNMTs) were used to investigate their involvement in the transcriptional regulation of SPARC expression and function. Results: In silico mapping of SPARC promoter identified consensus binding sites for subunits (RelA and NFκB1). Pharmacologic inhibition of NFκB as well as knockdown of p65-RelA and p50 subunits restored SPARC expression and function in ovarian cancer cells. Treatment of ovarian cancer cells with demethylating agent 5’-azacytidine and knockdown of DNMTs (DNMT1, DNMT3a and DNMT3b) indicated that NFκB-mediated SPARC repression is due to promoter methylation through DNMT3a. In ovarian cancer tissue microarrays, SPARC expression in cancer cells significantly and progressively decreased in advanced stage. The expression of SPARC in cancer cells inversely correlated with nuclear p65-RelA and DNMT3a expression. Conclusion: Our findings indicate that activated NFκB integrates inflammatory signals to exert epigenetic pressure suppressing tumor-SPARC through promoter methylation. Pharmacologic inhibitors of NFκB as well as anti-inflammatory agents may provide a significant therapeutic opportunity. Citation Format: Dylan P. Matthews, Sherine Taylor, Neveen A. Said. Epigenetic regulation of SPARC in ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1344.