Abstract GMM-022: IDH1 IS A PRO-SENESCENT THERAPY IN HIGH-GRADE SEROUS OVARIAN CANCER

Abstract

Abstract Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. High-grade serous carcinoma (HGSC) is the most frequently diagnosed and fatal histosubtype of EOC. We found that HGSC cell lines exhibit increased TCA cycle metabolites compared to fallopian tube cells, the proposed site of HGSC origin. Therefore, we propose that inhibition of TCA cycle metabolism may be a novel therapeutic strategy for HGSC. To determine which TCA cycle metabolism enzymes are dysregulated in ovarian cancer, we performed an unbiased qPCR screen of all 27 enzymes in the pathway. Our results indicate that isocitrate dehydrogenase I (IDH1) expression is significantly altered in EOC cell lines compared to fallopian tube cells. IDH1 catalyzes the conversion of isocitrate to alpha ketoglutarate (αKG) in a reversible reaction. It is well-known that IDH1 mutations play a role in cancer; however, recent publications suggest wildtype IDH1 overexpression promotes primary glioblastoma progression in the absence of mutation. Wildtype IDH1 and its role in metabolism and epigenetics has never been investigated in HGSC. To determine whether IDH1 plays a functional role in HGSC, we used both genetic and pharmacological approaches to suppress IDH1 in multiple HGSC cell lines. Knockdown or inhibition of IDH1 using the small molecule inhibitor GSK864 significantly decreased HGSC cell proliferation. Mechanistically, this was due to induction of senescence, a stable cell cycle arrest. We next aimed to determine the molecular mechanism underlying senescence induction due to inhibition of IDH1. Increased histone methylation of proliferation promoting genes (i.e., CCNA2 and PCNA) is a characteristic of senescence. αKG acts as a cofactor for the Jumonji C (JmjC) histone demethylase family, suggesting that suppression of αKG may affect the methylation status of histones. αKG levels were significantly decreased in IDH1 knockdown cells. Therefore, we hypothesized that decreasing αKG levels in HGSC may modulate the epigenome to induce senescence. Chromatin immunoprecipitation (ChIP) experiments showed an increase in repressive H3K9me2 histone methylation at proliferation-promoting gene loci (CCNA2 and PCNA) when IDH1 was knocked down. This correlated with a decrease in mRNA of both genes. These data suggest that knockdown of IDH1 induces senescence of HGSC cells by increased histone methylation of proliferation promoting genes. Finally, we aimed to determine the JmjC demethylase family member that is inhibited by IDH1 knockdown. The JmjC KDM4 family modulates histone demethylation of histone H3 lysine 9. KDM4A is upregulated in EOC and correlates with worse overall survival. Interestingly, knockdown studies of KDM4A phenocopied those of IDH1 knockdown. Future studies are aimed to dissect the role of KDM4A in senescence induction. Altogether, these data suggest that targeting the metabolic enzyme IDH1 in HGSC induces senescence through epigenetic reprogramming and may be a novel metabolic therapy for HGSC patients. Citation Format: Erika S Dahl, Nathaniel W Snyder, Katherine M Aird. IDH1 IS A PRO-SENESCENT THERAPY IN HIGH-GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-022.