Abstract 675: Jarid2 is a novel target for lung cancer therapy.

Abstract

Abstract Increasing evidence indicates that aberrant expression/activity of polycomb repressive-complex-2 (PRC-2) contributes to the pathogenesis of a variety of human malignancies including lung cancers. In recent studies we have demonstrated that depletion of EZH2- a core component of PRC-2, either by biochemical or pharmacologic techniques inhibits the malignant phenotype of lung cancer cells, indicating that PRC-2 is a target for epigenetic therapy of lung cancer. In the present study, we sought to further examine the potential efficacy of targeting PRC-2 in lung cancers via depletion of Jarid2, which modulates gene expression in stem cells in part via targeting PRC-2 to DNA. Quantitative RT-PCR and immunoblot experiments demonstrated over-expression of Jarid2 in cultured lung cancer cells and primary lung cancers relative to normal respiratory epithelia or histologically normal lung tissues. In subsequent experiments, shRNA techniques were used to inhibit Jarid2 expression in lung cancer cells. Quantitative RT-PCR and immunoblot experiments demonstrated that knock-down of Jarid2 had relatively modest effects on global H3K27Me3 levels in lung cancer cells. These finding were in contrast to knock-down of EZH2, which markedly inhibited H3K27 trimethylation in these cancer cells. Interestingly, knock-down of Jarid2 inhibited in vitro proliferation of lung cancer cells by approximately 70% relative to respective controls, and significantly diminished growth of subcutaneous lung cancer xenografts in athymic nude mice. The anti-proliferative effects of Jarid2 knock-down were relatively comparable to those observed following depletion of EZH2 in lung cancer cells. Jarid2 knock- down only modestly enhanced cytotoxicity mediated by DZNep in lung cancer cells. Microarray experiments are currently in progress to compare gene expression profiles in lung cancer cells mediated by Jarid2 knock-down relative to EZH2 depletion or DZNep treatment, and to delineate the mechanisms by which Jarid2 enhances the malignant phenotype of lung cancer cells. Collectively, these preliminary findings warrant further analysis of Jarid2 expression during pulmonary carcinogenesis, and suggest that Jarid2 may be a novel target for lung cancer therapy. Citation Format: Young K. Hong, Mary Zhang, Scott Atay, Manish Raiji, Trevor Upham, Julie A. Hong, Mahadev Rao, David S. Schrump. Jarid2 is a novel target for lung cancer therapy. [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 675. doi:10.1158/1538-7445.AM2013-675