Title: DRES-01. ROLE OF HISTONE LYSINE DEMETHYLASE KDM2B IN GLIOBLASTOMA TUMOR CELL MAINTENANCE AND CHEMORESISTANCE
Abstract: Glioblastoma (GBM) is the most deadly and malignant of all brain tumors in adults partly due to acquired resistance to conventional drugs leading to recurrence. Emerging evidence indicate that aberrant expression of epigenetic enzymes, resulting in altered gene transcription, may be responsible for cell maintenance and drug resistance in several cancers including GBM. In cancer, epigenetic inhibitors have been shown both to have direct anti-neoplastic functions as well as being able to sensitize cancer cells towards radio- and chemotherapy. As epigenetic dysregulation has been suggested to be involved in the progression and development of glioblastoma (GBM), regulation of epigenetic factors could potentially improve current treatments of GBM. A histone lysine demethylase enzyme termed KDM2B, a regulator of H3K36 methylation, is involved in cellular processes including transcription, cell growth, and DNA repair. In addition, recent studies have shown that KDM2B is involved in cell maintenance and tumorigenesis in leukemia, pancreatic cancer and breast cancer. In this study we sought to elucidate the role of KDM2B in GBM. In vitro assays performed on patient derived GBM cell cultures showed increased expression of KDM2B compared to normal brain tissue. Knockdown of KDM2B by siRNA resulted in induced apoptosis, attenuated cell growth, induction of DNA damage and increased sensitivity towards the conventional chemotherapies lomustine and etoposide. In parallel, chemical inhibition of KDM2B by a histone demethylase inhibitor (GSK-J4) lead to increased apoptosis, DNA damage and inhibition of GBM cell viability at low micro molar concentrations. Combined administration of GSK-J4 and the chemotherapies lomustine or etoposide displayed synergistic inhibition of GBM cell viability. In summary, our results indicate that KDM2B promotes GBM cell maintenance and chemoresistance, proposing KDM2B as a novel therapeutic target for the treatment of GBM.