Targeting MYC/HDAC2 interaction in Group 3 medulloblastoma – rationales for an innovative therapeutic approach

Introduction: Medulloblastoma (MB) is one of the most frequent malignant brain tumors in children. Four subgroups with different molecular characteristics as well as differing clinical courses have been identified. In patients with Group 3 MBs overall survival remains particularly poor despite multimodal treatment. Group 3 and Group 4 tumors are characterized by modifications of their chromatin organizing machinery. We here explore the interaction of transcription factor MYC as a driving force in Group 3 MB and the chromatin modifying class I histone deacetylases (HDACs). Methods: Expression of class I HDACs in MB compared to normal brain tissue was analyzed in gene expression profiles and tissue microarrays. MB cell lines were treated in vitro with HDAC inhibitors (HDACi) preferentially inhibiting class I HDACs such as vorinostat, panobinostat and MS-275. In addition, siRNA mediated knockdown of class I HDACs HDAC1 and HDAC2 was performed and the induced phenotype was characterized regarding metabolic activity, cell cycle, viability and caspase-3-like activity. Interaction of HDAC1, HDAC2 and MYC protein was analyzed by co-immunoprecipitation experiments. Results: HDAC2 is highly expressed in Group 3 MB tumors. Differential response of cell lines with different levels of MYC to class I HDAC inhibition suggests increased susceptibility of cells with MYC amplification and high levels of MYC protein to class I HDACi treatment. Knockdown of HDAC2 reduces the number of viable cells, increases caspase-3-like activity and increases the sub G0/G1 fraction in MYC amplified MB cell lines in vitro . Knockdown of HDAC2 as well as class I HDAC inhibition reduces levels of MYC mRNA and protein in vitro . HDAC2, but not HDAC1 is found in a complex with MYC protein in MYC amplified cell lines. Conclusion: High-risk patients with Group 3 MB tumors may benefit from class I HDACi treatment. Amplification of MYC and/or high levels of MYC may serve as predictive marker for HDACi treatment. The interaction of HDAC2 and MYC points towards a mechanistic explanation for this clinically highly relevant observation.