MB-57: INTERACTION OF HDAC2 AND MYC IN GROUP 3 MEDULLOBLASTOMA - A NOVEL THERAPEUTIC TARGET

Despite aggressive multimodal treatment, patients with high-risk subgroup medulloblastoma (MB) show poor overall survival rates and long-term survivors suffer from treatment-associated morbidity. In tumors of Group 3 MB patients amplification and high levels of the transcription factor MYC, a well known oncogenic driver, predict a particularly poor outcome. We have previously shown that MYC amplified Group 3 MB cell lines expressing high levels of MYC are highly susceptible to pan- and class I-histone deacetylase (HDAC) inhibitor treatment. We here explore the molecular mechanisms of the oncogenic addiction of MYC amplified Group 3 MB cell lines to class I HDAC2. A panel of established MB cell lines was used for cell culture experiments, including MYC amplified cell lines. Functional interaction between MYC and HDAC2 was investigated by enzymatic inhibition using class I-selective HDAC inhibitors (HDACi), by protein depletion using RNAi-mediated knockdown, and by rescue experiments with proteasome inhibitors. Co-localization studies of HDAC2 and MYC were performed using co-immunoprecipitation and mass spectrometry. Targeting HDAC2 with small molecule inhibitors as well as depletion of HDAC2 protein reduces MYC protein levels without alteration of MYC mRNA expression levels, indicating a post-translational regulation mechanism. MYC and HDAC2 are localized in a protein complex. Our data indicate that HDAC2 stabilizes MYC protein, and that class I HDACis contribute to destabilization of MYC protein. Rational combinatorial targeting of MYC/HDAC2 oncogene multi-protein complex is a novel strategy to treat group 3 medulloblastoma.