Glioblastoma Multiforme (GBM) is the most common and aggressive brain tumor, which lacks efficient therapy. TRAIL is an antitumor agent that triggers apoptosis selectively on tumor cells, thus can be utilized as therapeutic approach for GBM. However, most GBM cells confer TRAIL resistance and how this resistance is regulated at a molecular level is not completely clear. Epigenetic deregulation has been increasingly recognized as a hallmark of cancer. In this study, we conducted a drug screen against selected chromatin modifiers in U87MG GBM cells and identified Belinostat, Trichostatin A and Chaetocin as potential apoptosis regulators. While Belinostat and Trichostatin A are well-characterized histone deacetylase inhibitors in the context of malignancies, Chaetocin’s role in cancers is less well-known and its relation to TRAIL is novel. Chaetocin is a fungal mycotoxin that inhibits Suv39H1, a histone methyltransferase (HMT) that catalyzes H3K9 methylation. In this study, we investigated how Chaetocin affects the response of GBM cells to apoptotic stimuli by TRAIL. To this end, GBM cell lines U87MG and U373 are treated with varying dose of Chaetocin and cells’ viability and apoptosis responses to varying doses of TRAIL are analyzed. Chaetocin decreased viability down to 11% of control in U87MG cells upon TRAIL treatment, without inducing cellular toxicity and apoptosis by itself. Chaetocin was shown to upregulate the expression of proapoptotic genes while downregulating antiapoptotic gene expression. In addition, elevated Caspase3/7, Caspase8 and Caspase9 activities were detected in U87MG upon Chaetocin treatment together with PARP cleavage as indicator of apoptosis. Chaetocin also sensitized GBM cells to BH3 mimetic ABT263 which indicates that sensitization of GBM cells by Chaetocin is not limited to TRAIL but is rather a general phenomenon for apoptosis. We infer from these findings that Chaetocin plays critical and specific role in apoptotic pathway. Our future work is directed towards examining the changes in gene expression profiling of GBM cells upon Chaetocin treatment and understanding the functional role of H3K9 Methylation in GBM cell apoptosis. To this end, RNAseq analysis is currently being performed and expected to enlighten Chaetocin’s mechanism of action. These findings support our motivation that identifying epigenetic modifier drugs as apoptosis sensitizer may be a promising therapeutic approach for GBM treatment.

Note: This abstract was not presented at the meeting.

Citation Format: Ezgi Özyerli, Zeynep Kahya Yeşil, Udo Oppermann, Tuğba Bağcı Önder. Chaetocin sensitizes GBM cells to TRAIL and BH3 mimetics induced apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5873. doi:10.1158/1538-7445.AM2017-5873