Abstract A35: Targeting the IDH1-mediated metabolic-epigenetic axis in cyclin E-high ovarian cancer
Authors: Erika S. Dahl, Raquel Buj, Qingyuan Jia, Kelly E. Leon, Katherine M. Aird
Journal: Clinical Cancer Research (2020)

Abstract Cyclin E is an oncogene that is overexpressed in approximately 20% of high-grade serous ovarian carcinomas (HGSOC) and is associated with worse survival and resistance to DNA-damaging agents due to homologous recombination (HR) proficiency. Additionally, cyclin E is considered an initiating factor in the transformation of fallopian tube cells, the cell of origin of HGSOC. In normal cells, increased cyclin E induces replication stress and subsequent DNA damage that leads to cellular senescence, a state of cell cycle arrest. Previous studies demonstrated that cyclin E overexpression in fallopian tube increases expression of DNA damage response (DDR) genes. This presumably allows for tolerance of replication stress, repair of DNA damage, and bypass of senescence. However, the mechanism by which cyclin E-high cells bypass senescence and increase DDR gene expression remains unclear. We previously published that the TCA cycle enzyme isocitrate dehydrogenase I (IDH1) is high in HGSOC cells compared to fallopian tube. Importantly, IDH1 is critical for HGSOC cell proliferation as knockdown or inhibition of IDH1-induced senescence through increased repressive histone H3K9me2 at multiple proliferation-promoting gene loci. Excitingly, we observed a positive correlation between high cyclin E expression and high IDH1 in both fallopian tube and HGSOC cells. Indeed, overexpression of cyclin E increased IDH1 expression in both fallopian tube and HGSOC cells. Therefore, we hypothesized that upregulation of IDH1 in cyclin E high cells increases DDR gene expression by altering the epigenetic landscape and thereby suppressing senescence induction. Our data demonstrate that IDH1 overexpression in fallopian tube phenocopies cyclin E overexpression by increasing expression of several DDR genes, including BRCA2. Indeed, knockdown of IDH1 in cyclin E-high cells decreased DDR gene expression, demonstrating that IDH1 is necessary for DDR gene expression in cyclin E-high cells. Mechanistically, we determined that this is through a metabolic-epigenetic axis, which regulates occupancy of repressive H3K9 methylation at DDR gene loci. Finally, to determine whether the alteration in DDR gene expression is functionally relevant, we treated cyclin E-high PARPi-resistant cells with an IDH1 inhibitor. While neither inhibitor affected proliferation of cyclin E-high HGSOC cells alone, the combination was highly synergistic, suggesting that the IDH1 inhibitor converted HR-proficient cyclin E-high cells to an HR-deficient phenotype. Together, our data suggest that IDH1-mediated metabolism affects the epigenome in cyclin E-high cells, which contributes to both fallopian tube transformation and HR proficiency. Targeting IDH1 with currently FDA-approved inhibitors may therefore be a rational therapeutic strategy for cyclin E-high HGSOC patients. Citation Format: Erika S. Dahl, Raquel Buj, Qingyuan Jia, Kelly E. Leon, Katherine M. Aird. Targeting the IDH1-mediated metabolic-epigenetic axis in cyclin E-high ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A35.