MYC–MIZ1-mediated repression of target genes is essential in group 3 (G3) medulloblastoma.
Major finding: MYC–MIZ1-mediated repression of target genes is essential in group 3 (G3) medulloblastoma.
Concept: MYCN and c-MYC are differentially expressed in medulloblastoma subtypes and differ in MIZ1 binding.
Impact: Blocking MYC–MIZ1-mediated transcriptional repression may be beneficial in G3 medulloblastoma.
Medulloblastomas frequently have overexpression or amplification of MYC genes, which are differentially expressed in the four subtypes of this disease. WNT and group 3 (G3) medulloblastomas express high levels of c-MYC (MYC), whereas sonic hedgehog (SHH) and group 4 (G4) medulloblastomas overexpress MYCN. MYC activates transcription when dimerized with MAX, but represses transcription when in complex with MIZ1. MYC promotes self-renewal of neural progenitor cells through MIZ1 binding, and G3 medulloblastoma cells are more stem-like than the other medulloblastoma subtypes. Therefore, Vo, Wolf, and colleagues hypothesized that distinct MYC and MYCN protein partners might underlie the different medulloblastoma subtypes. Mice transplanted with granule neuron progenitors (GNP) expressing a MYC mutant with reduced ability to bind MIZ1 (MYCVD) exhibited delayed tumor formation compared with expression of wild-type MYC. Additionally, the morphology and pathology of MYC tumors, but not MYCVD tumors, was similar to G3 medulloblastoma, suggesting that interaction with MIZ1 is essential in G3 medulloblastoma. In tumorspheres, MYCVD cells proliferated more slowly and exhibited higher levels of apoptosis. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) indicated that MYC and MIZ1 had largely overlapping binding sites in G3 medulloblastomas, and medulloblastoma. MYC–MIZ1complexes repressed genes involved in ciliogenesis, neuronal differentiation, and survival. MIZ1 bound more strongly to MYC than MYCN, and ChIP-seq revealed that, in G3 medulloblastomas, MIZ1 occupancy of MYC binding sites was increased compared to SHH medulloblastoma. Further, analysis of expression data sets indicated that genes repressed by MYC and MIZ1 were upregulated in GNPs and mouse SHH medulloblastomas, suggesting that G3 medulloblastomas are defined by MYC–MIZ1 complex–driven gene repression. Together, these findings suggest that the MYC–MIZ1 interaction can distinguish G3 medulloblastoma from other subtypes, and indicate that MYC and MYCN have distinct functions in medulloblastoma.