Abstract 674: The lysine demethylase KDM1 is a novel therapeutic target for the treatment of gliomas.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Glioma development is a multistep process, involving alterations in genetic and epigenetic mechanisms. Understanding the mechanisms and enzymes that promote epigenetic changes in gliomas are urgently needed to identify novel therapeutic targets. In the present study we explored the significance of histone demethylase KDM1 in glioma progression. In order to know the status of expression of KDM1, we utilized glioma tissue microarrays which consist of different grades of astrocytomas, oligodendrogliomas, ependymomas and normal brain tissues. Immunohistochemical analysis showed that KDM1 expression is overexpressed in the gliomas compared to normal brain, and KDM1 expression levels were positively correlated with histological malignancy. KDM1 expression was also found to be elevated in various established glioma cell lines. To study the functional significance of KDM1 in gliomas, KDM1 expression was silenced using siRNA or its pharmacological inhibition using pargyline or NCL-1. Silencing of KDM1 or inhibition of its enzyme activity significantly reduced the proliferation and colony formation of glioma cells. Mechanistic studies showed that inhibition of KDM1 promoted the acetylation of p53 and up regulation of its target genes p21 and PUMA. Patient-derived primary GBM cells expressed high levels of KDM1 and pharmacological inhibition of KDM1 decreased their proliferation. Further, KDM1 inhibition reduced the expression of stemness markers CD133 and nestin in GBM cells. Mouse xenograft assays revealed that inhibition of KDM1 using pargyline significantly reduced U87 glioma xenograft tumor growth. Inhibition of KDM1 increased levels of H3K4-me2 and H3K9-Ac histone modifications, reduced H3K9-me2 modification and promoted expression of p53 target genes (p21 and PUMA), leading to apoptosis of glioma xenograft tumors. Our results suggest that KDM1 is overexpressed in gliomas and could be a potential therapeutic target for the treatment of gliomas. Citation Format: Gangadhara R. Sareddy, Sandeep Saran, Binoj C. Nair, Samaya R. Krishnan, Vijay K. Gonugunta, Andrew J. Brenner, Ratna K. Vadlamudi. The lysine demethylase KDM1 is a novel therapeutic target for the treatment of gliomas. [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 674. doi:10.1158/1538-7445.AM2013-674