MBRS-23. EFFECT OF KNOCKDOWN OF KDM6A BY CRISPR/CAS9 EDITING IN MEDULLOBLASTOMA. Issue 2 (22nd June 2018)

• Record Type: Journal Article
• Authors: Fosmire, Susan; Joshi, Molishree; Smith, Tim; Venkataraman, Sujatha; Vibhakar, Rajeev
• Is Part Of: Neuro-oncology. Volume 20:Issue 2(2018)supplement 2
• Page Start: i133
• Page End: i133
• Publication Date: 2018-06-22
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy059.468
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: KDM6A and EZH2 are epigenetic regulators that play a key role in embryogenesis and development. Presumably, EZH2 and KDM6A have opposite impact on H3K27me3. KDM6A functions as a demethylase of Histone3 lysine 27 trimethylation and is closely associated with the mixed lineage leukemia 2/3 in creating a transcriptionally active chromatin state through removal of methyl groups. EZH2, on the other hand, is a methyl transferase which catalyzes the trimethylation of Histone3 lysine 27. Several studies including ours have shown that KDM6A is genomically deleted in Group 4 medulloblastoma suggesting it may have a role as a tumor suppressor. The biological role of KDM6A in medulloblastoma is not clear. To better understand the role of KDM6A in MB, in our current study we used the Crispr/Cas9 system to knock out KDM6A in MB cell lines and to determine the effect of KDM6A on MB tumor cell stemness and proliferation. Increased expression of stemcell-associated genes including Nanog, Nestin and Oct4 were observed in cells depleted of KDM6A. Intriguingly, Crispr/Cas9-mediated deletion of KDM6A significantly abolished MB cell neurosphere formation and cell proliferation compared to control cells. As expected, in the knockdown cells there was a concomitant increase in H3K27me3 and decrease in H3K4me3 expression but the overall biological impact of KDM6A deletion was unexpected. This puzzling effect on cells with the knockdown of KDM6A opens a door to investigate the target genes that are affected by the depletion of KDM6A. This study will shine light on new epigenetic therapies in medulloblastoma.