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

Dev Cell. 2017 Dec 18;43(6):673-688.e5. doi: 10.1016/j.devcel.2017.10.011. Epub 2017 Nov 2.

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.

Keywords: 4EBP1; Hedgehog; Smoothened; brain tumor; cerebellum; granule neuron; mTOR; mTORC1; medulloblastoma; translation.

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Cell Proliferation / physiology
  • Cerebellar Neoplasms / genetics
  • Cerebellar Neoplasms / metabolism*
  • Cerebellar Neoplasms / pathology
  • Eukaryotic Initiation Factors
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Humans
  • Kruppel-Like Transcription Factors / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Medulloblastoma / genetics
  • Medulloblastoma / metabolism*
  • Medulloblastoma / pathology
  • Mice
  • Phosphoproteins / antagonists & inhibitors*
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction / genetics
  • Smoothened Receptor / genetics
  • Smoothened Receptor / metabolism
  • Zinc Finger Protein Gli2 / genetics
  • Zinc Finger Protein Gli2 / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Eif4ebp1 protein, mouse
  • Eukaryotic Initiation Factors
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Phosphoproteins
  • Repressor Proteins
  • Smoothened Receptor
  • Zinc Finger Protein Gli2
  • Mechanistic Target of Rapamycin Complex 1