MBRS-12. INTERFERENCE WITH THE FUNCTION OF MYC IN GROUP 3 MEDULLOBLASTOMA. Issue 2 (22nd June 2018)

• Record Type: Journal Article
• Authors: Ecker, Jonas; Thatikonda, Venu; Oehme, Ina; Valinciute, Gintvile; Selt, Florian; Buhl, Juliane L; Usta, Diren; Tilburg, Cornelis M van; Herold-Mende, Christel; Schnölzer, Martina; Warnken, Uwe; Kool, Marcel; Jäger, Natalie; Pfister, Stefan M; Witt, Olaf; Milde, Till
• Is Part Of: Neuro-oncology. Volume 20:Issue 2(2018)supplement 2
• Page Start: i130
• Page End: i130
• 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/noy059.457
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: High-risk medulloblastoma (MB) is a deadly disease with poor overall survival. Survivors suffer from severe treatment-associated morbidity. Patients with Group 3 MB with an amplification of MYC show particularly poor outcome. Therefore novel therapies tailored to this subgroup are urgently needed. We have previously shown that MYC amplified MB cell lines are highly susceptible to inhibition of class I histone deacetylases (HDACs), including HDAC2. We here explore the functional interaction of HDAC2 and MYC. METHODS: Chromatin immunoprecipitation with pulldown of MYC, HDAC2, RNApolII and H3K27ac, followed by DNA-sequencing was performed in n=3 primary MYC amplified Group 3 MB tumors and correlated with gene expression profiles (GEP). The GEP of MYC amplified MB cell line HD-MB03 was determined after class I HDAC inhibition. MYC stability upon HDACi treatment was assessed in immunofluorescence microscopy and cycloheximide chase experiments. MYC-HDAC2 interaction was analyzed in co-immunoprecipitation and mass spectrometry studies. RESULTS: In primary tumors 90% of MYC DNA binding sites are co-occupied by HDAC2. Compared to MYC- or HDAC2-only bound genes, MYC-HDAC2 co-bound genes show strong recruitment of RNApolII and higher expression levels. In HD-MB03 cells MYC and HDAC2 show overlapping DNA binding sites of 80%, both proteins are co-localized in a multi-protein complex. GEP analysis revealed a significant downregulation of MYC target genes after treatment with class I HDAC inhibitor MS-275, coinciding aberrant MYC protein levels. Our data suggests that MYC functions directly depend on class I HDAC activity. Inhibiting HDAC2 may offer a therapeutic option to target the currently undruggable oncoprotein MYC.