Effect of Histone Deacetylase Inhibition on Ovarian Cancer Cell Survival

Abstract

An estimated 15.5 million Americans have or are currently in remission from cancer and this number is likely to rise to 20.3 million by 2026 (Kimberly et al., 2017). Drug resistance is a major issue during cancer therapy. Therefore, there is a constant need for novel chemotherapy agents for all cancer types including ovarian cancer (Ma et al., 2014, Seguin et al., 2015). Ovarian cancer is the 5th leading cause of cancer-related death among women and, in 2018 alone; there were an estimated 14070 deaths (Torre et al., 2018). In the past several years, gene-regulatory chemotherapeutic agents that act on the epigenetic mechanisms have drawn considerable interest as a potentially important class of anti-cancer treatment. Due to the complexity of cell cycle, proliferation and apoptotic processes involved in cancer progression, the identification of specific gene controlling proteins is highly desirable for targeted therapy. In this study, I determined that histone deacetylase 3 (HDAC3) or histone deacetylase 8 (HDAC8) inhibition caused cell death in ovarian cancer cell lines with a similar effectiveness as generic pan-HDAC inhibition. Firstly, pan-HDAC inhibition was compared to HDAC class specific and HDAC protein specific inhibition with HDAC3 or HDAC8 inhibition causing cell death as indicated by elevated protein levels of the apoptosis indicator cleaved caspase 3. Next, the cellular pathways associated with HDAC3 or HDAC8 inhibition were interrogated. Both HDAC3 and HDAC8 inhibition caused upregulation of DNA damage markers, while HDAC3 inhibition also caused upregulation of unfolded protein response markers. Additionally, HDAC3 or HDAC8 inhibition combined with Bcl-xL inhibition had a synergistic effect on the percentage of dead cells post treatment. Finally, HDAC3 and HDAC8 inhibition were tested on multiple cell lines with HDAC3 inhibition causing cell death in all ovarian cancer cells line and a lung cancer cell line while and HDAC8 inhibition only causing cell death in ovarian cancer cell lines.