P03.16.A ROLE OF BRD9 IN REGULATING RADIOTHERAPY INDUCED CHANGES IN CHROMATIN ARCHITECTURE OF GBM

Abstract

Abstract Glioblastoma (GBM) is the most common, formidable, and aggressive type of adult brain tumor, with a poor prognosis. The standard treatment strategies are surgical resection, followed by radiotherapy and accompanying chemotherapy. However, 90% of patients suffer from recurrence of the disease due to the radiation resistance and chemotherapy resistance of glioblastoma cells, which exacerbate the success of the treatment, and thus, resistance remains one of the most important obstacles to overcome. The advances in molecular biology revealed that therapy resistance is related with alterations in DNA repair pathways as well as epigenetic changes governed by histone modifications and chromatin remodeling. Therefore, understanding the underlying epigenetic mechanisms that are involved in the DNA damage response has the potential to develop effective therapeutic strategies. In this manner, an epigenetic drug screen is conducted to identify novel epigenetic modifiers and their inhibitors as radiosensitizers. Bromodomain containing 9 (BRD9) was selected as target modifier while iBRD9 is selected as the radiosensitizer. Inhibition of BRD9 with a common probe, iBRD9 reduced cell viability and colony formation when combined with different doses of radiotherapy. Also, as an acetylated histone reader, inhibition of BRD9 increased the number of acetylated histones as shown by Western Blotting; where Belinostat treatment served as positive control. Currently, our efforts are directed towards understanding which genes are directly targeted by BRD9 in the presence and absence of radiotherapy. To this end, we have ectopically expressed Flag-tagged BRD9 and confirmed its expression by Western Blots. We showed that BRD9 was mainly localized to nucleus. Using this tool, we will perform ChIP sequencing and reveal radiotherapy induced changes in BRD9 binding sites.