mTORC1-Mediated Inhibition of 4EBP1 Is Essential for Hedgehog Signaling-Driven Translation and Medulloblastoma

Chang Chih Wu, Shirui Hou, Brent A. Orr, Bryan R. Kuo, Yong Ha Youn, Taren Ong, Fanny Roth, Charles G. Eberhart, Giles W. Robinson, David J. Solecki, Makoto M. Taketo, Richard J. Gilbertson, Martine F. Roussel, Young Goo Han

Research output: Contribution to journalArticlepeer-review

Abstract

Mechanistic target of rapamycin (MTOR) cooperates with Hedgehog (HH) signaling, but the underlying mechanisms are incompletely understood. Here we provide genetic, biochemical, and pharmacologic evidence that MTOR complex 1 (mTORC1)-dependent translation is a prerequisite for HH signaling. The genetic loss of mTORC1 function inhibited HH signaling-driven growth of the cerebellum and medulloblastoma. Inhibiting translation or mTORC1 blocked HH signaling. Depleting 4EBP1, an mTORC1 target that inhibits translation, alleviated the dependence of HH signaling on mTORC1. Consistent with this, phosphorylated 4EBP1 levels were elevated in HH signaling-driven medulloblastomas in mice and humans. In mice, an mTORC1 inhibitor suppressed medulloblastoma driven by a mutant SMO that is inherently resistant to existing SMO inhibitors, prolonging the survival of the mice. Our study reveals that mTORC1-mediated translation is a key component of HH signaling and an important target for treating medulloblastoma and other cancers driven by HH signaling. Wu et al. show that Hedgehog (HH) signaling promotes protein synthesis via a non-canonical, mTORC1/4EBP1-dependent pathway and that mTORC1/4EBP1-dependent translation is a prerequisite for canonical HH signaling. They show further that inhibition of mTORC1 signaling suppresses HH-dependent cerebellar growth and the development of HH-driven medulloblastoma.

Original languageEnglish (US)
Pages (from-to)673-688.e5
JournalDevelopmental Cell
Volume43
Issue number6
DOIs
StatePublished - Dec 18 2017

Keywords

  • 4EBP1
  • Hedgehog
  • Smoothened
  • brain tumor
  • cerebellum
  • granule neuron
  • mTOR
  • mTORC1
  • medulloblastoma
  • translation

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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