Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation.
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.
Canettieri
Gianluca
G
Department of Experimental Medicine, Sapienza University, 324 viale Regina Elena, 00161 Rome, Italy.
Di Marcotullio
Lucia
L
Greco
Azzura
A
Coni
Sonia
S
Antonucci
Laura
L
Infante
Paola
P
Pietrosanti
Laura
L
De Smaele
Enrico
E
Ferretti
Elisabetta
E
Miele
Evelina
E
Pelloni
Marianna
M
De Simone
Giuseppina
G
Pedone
Emilia Maria
EM
Gallinari
Paola
P
Giorgi
Alessandra
A
Steinkühler
Christian
C
Vitagliano
Luigi
L
Pedone
Carlo
C
Schinin
M Eugenià
ME
Screpanti
Isabella
I
Gulino
Alberto
A
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
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