Glioblastoma multiforme 'de apoptoz direncini regüle eden epigenetik faktörlerin belirlenmesi

Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain tumor. Despite recent developments in surgery, chemo- and radiotherapy, the prognosis of GBM patients is extremely poor, highlighting an urgent need for novel treatment strategies. TNF-Related Apoptosis Inducing Ligand (TRAIL) is a potent anti-cancer agent that can induce apoptosis selectively in cancer cells by activating death receptor signaling. GBM cells frequently develop resistance to TRAIL, which renders clinical application of TRAIL therapeutics inefficient. Accumulating evidence suggest that death receptor pathway components can be regulated at a transcriptional level, especially through epigenetic silencing of pro-apoptotic mediators. Therefore, understanding the epigenetic mechanisms of apoptotic response is critical for better design of pro-apoptotic therapies for cancer. To this end, we undertook a chemical strategy to interrogate the roles of chromatin modifiers in GBM cell apoptosis. We identified Chaetocin, a fungal metabolite and an inhibitor of histone methyl transferase SUV39H1, as a novel TRAIL sensitizer. Combining low subtoxic doses of Chaetocin and TRAIL resulted in very potent and rapid apoptosis of GBM cells. Chaetocin also effectively sensitized GBM cells to further pro-apoptotic agents, such as FasL and BH3 mimetics. Chaetocin mediated apoptosis sensitization was achieved through Reactive Oxygen Species (ROS) generation and consequent DNA damage induction that involved TP53 activity. Chaetocin induced transcriptomic changes showed activation of antioxidant defense mechanisms and DNA damage response pathways. Heme Oxygenase 1 (HMOX1) was among the top upregulated genes, whose induction was ROS-dependent. Finally, Chaetocin and TRAIL combinatorial treatment revealed efficacy in vivo. Taken together, our results provide a novel role for Chaetocin as an apoptosis priming agent. Discovery of epigenetic factors modulating tumor drug response and survival via high throughput, robust and affordable screens such as our chemical screen will ultimately lead to rapid development of effective therapies.