title: Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation.
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.
authors.affiliation: Department of Experimental Medicine, Sapienza University, 324 viale Regina Elena, 00161 Rome, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Canettieri
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
authors.forename: Azzura
authors.initials: A
authors.lastname: Greco
authors.forename: Sonia
authors.initials: S
authors.lastname: Coni
authors.forename: Laura
authors.initials: L
authors.lastname: Antonucci
authors.forename: Paola
authors.initials: P
authors.lastname: Infante
authors.forename: Laura
authors.initials: L
authors.lastname: Pietrosanti
authors.forename: Enrico
authors.initials: E
authors.lastname: De Smaele
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.forename: Evelina
authors.initials: E
authors.lastname: Miele
authors.forename: Marianna
authors.initials: M
authors.lastname: Pelloni
authors.forename: Giuseppina
authors.initials: G
authors.lastname: De Simone
authors.forename: Emilia Maria
authors.initials: EM
authors.lastname: Pedone
authors.forename: Paola
authors.initials: P
authors.lastname: Gallinari
authors.forename: Alessandra
authors.initials: A
authors.lastname: Giorgi
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkühler
authors.forename: Luigi
authors.initials: L
authors.lastname: Vitagliano
authors.forename: Carlo
authors.initials: C
authors.lastname: Pedone
authors.forename: M Eugenià
authors.initials: ME
authors.lastname: Schinin
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
mesh_terms: D000107:Acetylation; D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D021241:Spectrometry, Mass, Electrospray Ionization; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014166:Transferases; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
chemical_list: D018797:Cell Cycle Proteins; D044842:Cullin Proteins; C498520:Gli1 protein, mouse; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; C466095:Kctd11 protein, mouse; D014166:Transferases; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases