The Interaction of Myc with Miz1 Defines Medulloblastoma Subgroup Identity

Cancer Cell. 2016 Jan 11;29(1):5-16. doi: 10.1016/j.ccell.2015.12.003.

Abstract

Four distinct subgroups of cerebellar medulloblastomas (MBs) differ in their histopathology, molecular profiles, and prognosis. c-Myc (Myc) or MycN overexpression in granule neuron progenitors (GNPs) induces Group 3 (G3) or Sonic Hedgehog (SHH) MBs, respectively. Differences in Myc and MycN transcriptional profiles depend, in part, on their interaction with Miz1, which binds strongly to Myc but not MycN, to target sites on chromatin. Myc suppresses ciliogenesis and reprograms the transcriptome of SHH-dependent GNPs through Miz1-dependent gene repression to maintain stemness. Genetic disruption of the Myc/Miz1 interaction inhibited G3 MB development. Target genes of Myc/Miz1 are repressed in human G3 MBs but not in other subgroups. Therefore, the Myc/Miz1 interaction is a defining hallmark of G3 MB development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebellar Neoplasms / metabolism*
  • Cerebellar Neoplasms / pathology*
  • Gene Expression Regulation, Neoplastic
  • Hedgehog Proteins / genetics
  • Medulloblastoma / metabolism*
  • Mice
  • Neurons / metabolism*
  • Nuclear Proteins / metabolism*
  • Protein Inhibitors of Activated STAT / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction / genetics
  • Ubiquitin-Protein Ligases

Substances

  • Hedgehog Proteins
  • Nuclear Proteins
  • Protein Inhibitors of Activated STAT
  • Proto-Oncogene Proteins c-myc
  • Miz1 protein, mouse
  • Ubiquitin-Protein Ligases