The ultimate goal of this F31 Ruth L. Kirchstein NRSA is to request support to address a fundamental gap in knowledge on the role of metabolism in regulation the epigenetic landscape of the senescence microenvironment (termed the senescence-associated secretory phenotype; SASP) and its contribution to the cancer stem cell (CSC) population and chemoresistance in epithelial ovarian cancer (EOC). The F31 Ruth L. Kirschstein NRSA support will help further contribute to my scientific training and pathway to becoming an independent researcher in academia. This research proposal focuses on experimentally and mechanistically determining how alteration in the metabolite alpha-ketoglutarate (a-KG) regulates the Jumonji-C (JmjC) histone demethylase KDM2B, which in turn modulates the SASP. Additionally, the proposal aims to determine whether alterations in KDM2B expression will reduce detrimental paracrine effects of the SASP. The proposed studies are based on my preliminary findings suggesting that the active histone mark, H3K79me3, along with expression of SASP-related genes, are increased upon cisplatin-induced senescence in EOC cells. Additionally, a-KG is decreased in cisplatin-induced senescent cells, and supplementation of these cells with exogenous a-KG suppresses the SASP. Furthermore, preliminary data indicate that the paracrine effects of the SASP contribute to increased cancer stem cells. I will continue addressing results obtained in my preliminary data in the following specific aims: 1) to determine the molecular mechanism by which SASP gene expression is epigenetically regulated through H3K79 tri- methylation in EOC and the contribution of a-KG to this process; and 2) to determine whether the paracrine effects of the SASP contributes to increased cancer stem cell population and chemoresistance of EOC. These studies will provide a novel mechanism for understanding how the SASP is epigenetically regulated and how it contributes to EOC chemoresistance and tumor progression.
Approximately 70% of ovarian cancer patients treated with the standard-of-care platinum-based chemotherapeutics relapse and develop chemoresistant disease. Platinum-based therapies result in therapy- induced senescence (TIS), which can have detrimental side effects due to the senescence-associated secretory phenotype (SASP). In this study, I will investigate the metabolic-epigenetic regulation of the SASP. The results will have a direct impact on the development of novel therapeutic strategies to obtain a sustain therapeutic response to platinum.
