Reduced chromatin binding of MYC is a key effect of HDAC inhibition in MYC amplified meduloblastoma [expression]

MYC is a driver oncogene in many cancers. Inhibition of MYC promises high therapeutic potential, but specific MYC inhibitors remain unavailable for clinical use. Previous studies suggest that MYC amplified Medulloblastoma cells are vulnerable to HDAC inhibition. Using co-immunoprecipitation, mass spectrometry and ChIP-sequencing we show that HDAC2 is a cofactor of MYC in MYC amplified primary medulloblastoma and cell lines. The MYC-HDAC2 complex is bound to genes defining the MYC-dependent transcriptional profile. Class I HDAC inhibition leads to stabilization and reduced DNA binding of MYC protein inducing a down-regulation of MYC activated genes (MAGs) and up-regulation of MYC repressed genes (MRGs). MAGs and MRGs are characterized by opposing biological functions and distinct E-box distribution. We conclude that MYC and HDAC2 (class I) are localized in a complex in MYC amplified medulloblastoma and drive a MYC-specific transcriptional program, which is reversed by the class I HDAC inhibitor entinostat. Thus, the development of HDAC inhibitors for treatment of MYC amplified medulloblastoma should include HDAC2 in its profile in order to directly target MYC´s trans-activating and trans-repressing function.

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Ecker J, Thatikonda V, Sigismondo G, Selt F, Valinciute G, Oehme I, Müller C, Buhl JL, Ridinger J, Usta D, Qin N, van Tilburg CM, Herold-Mende C, Remke M, Sahm F, Westermann F, Kool M, Wechsler-Reya RJ, Chavez L, Krijgsveld J, Jäger N, Pfister SM, Witt O, Milde T