Abstract 5143: KDM3A promotes cell growth and cisplatin-resistance in ovarian cancer cells

Abstract

Abstract Background: Ovarian cancer is the most lethal gynecological cancer affecting the women worldwide. One of the main challenging hurdles in ovarian cancer treatment is the high recurrence rate due to therapeutic resistance. Recent evidences showed that JmjC-domain (JMJD) containing histone demethylases plays a critical role in controlling gene expression during normal development and cancer progression. Aims: To determine whether histone demethylase plays a role in ovarian cancer progression and therapeutic resistance. Methods: We developed cisplatin-resistance ovarian cancer cell lines SKOV-3 and OVCAR-5 and isolated total RNA to screen the expression pattern of JMJD family genes by real-time RT-PCR. We performed stable knock-down of KDM3A by lentiviral mediated ShRNA transfection and studied its effects on cell proliferation and apoptosis by MTT assay and western blot analysis (PARP, caspase-3), respectively. We also determined the effect of KDM3A knock-down on cell cycle and apoptosis regulators by western blot. Results: Our observations indicated the differential expression of various JMJD family proteins between cisplatin-resistance and sensitive cell lines. To further evaluate our results, we also tested the expression of those differentially expressed JMJD proteins in a widely used cisplatin-resistance and sensitive A2780 cell lines. We observed that KDM3A/JMJD1A is consistently overexpressed in all the cisplatin-resistance cell lines studied. Next, we stably knock-down KDM3A in cisplatin-resistance OVCAR-5 and A2780 cell lines. More interestingly, we found that KDM3A depletion inhibited cell proliferation, induced apoptosis and enhanced the sensitivity to cisplatin treatment. Further, we confirmed that the important regulators of cell cycle and apoptosis including p21 and Bcl-2 were modulated by KDM3A knock-down. Conclusions: Our results indicate that KDM3A is a critical epigenetic factor required for the ovarian cancer growth by promoting cell proliferation and cisplatin-resistance. Our findings might have important clinical implications in targeting ovarian cancer cells by using specific histone demethylase inhibitors. Grant support: This work was supported by Carl and Roberta Deutsch, and Kelly Day Foundations. Citation Format: Sivakumar Ramadoss, Suvajit Sen, Gautam Chaudhuri, Robin Farias-Eisner. KDM3A promotes cell growth and cisplatin-resistance in ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5143. doi:10.1158/1538-7445.AM2014-5143