Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation

Nat Cell Biol. 2010 Feb;12(2):132-42. doi: 10.1038/ncb2013. Epub 2010 Jan 17.

Abstract

Hedgehog signalling is crucial for development and is deregulated in several tumours, including medulloblastoma. Regulation of the transcriptional activity of Gli (glioma-associated oncogene) proteins, effectors of the Hedgehog pathway, is poorly understood. We show here that Gli1 and Gli2 are acetylated proteins and that their HDAC-mediated deacetylation promotes transcriptional activation and sustains a positive autoregulatory loop through Hedgehog-induced upregulation of HDAC1. This mechanism is turned off by HDAC1 degradation through an E3 ubiquitin ligase complex formed by Cullin3 and REN, a Gli antagonist lost in human medulloblastoma. Whereas high HDAC1 and low REN expression in neural progenitors and medulloblastomas correlates with active Hedgehog signalling, loss of HDAC activity suppresses Hedgehog-dependent growth of neural progenitors and tumour cells. Consistent with this, abrogation of Gli1 acetylation enhances cellular proliferation and transformation. These data identify an integrated HDAC- and ubiquitin-mediated circuitry, where acetylation of Gli proteins functions as an unexpected key transcriptional checkpoint of Hedgehog signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism*
  • Electrophoresis, Polyacrylamide Gel
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase 2 / genetics
  • Histone Deacetylase 2 / metabolism
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Medulloblastoma / genetics
  • Medulloblastoma / metabolism
  • Mice
  • NIH 3T3 Cells
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Protein Binding
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Spectrometry, Mass, Electrospray Ionization
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Zinc Finger Protein GLI1
  • Zinc Finger Protein Gli2

Substances

  • Cullin Proteins
  • Gli1 protein, mouse
  • Gli2 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • Oncogene Proteins
  • Trans-Activators
  • Zinc Finger Protein GLI1
  • Zinc Finger Protein Gli2
  • Kctd11 protein, mouse
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histone Deacetylases