Histone deacetylase and cullin3–renkctd11 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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution

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about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THE HIRA COMPLEX REGULATES GLI3R-DEPENDENT TRANSCRIPTION IN HEDGEHOG

SIGNALING AND MEDULLOBLASTOMA CELL GROWTH AND MIGRATION Article Open access 02 January 2025 SMURF1 AND SMURF2 DIRECTLY TARGET GLI1 FOR UBIQUITINATION AND PROTEASOME-DEPENDENT DEGRADATION

Article Open access 18 December 2024 EPIGENETIC AND MOLECULAR COORDINATION BETWEEN HDAC2 AND SMAD3-SKI REGULATES ESSENTIAL BRAIN TUMOUR STEM CELL CHARACTERISTICS Article Open access 19

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thank M. P. Scott for the gift of _Ptch1__−/−_ cells, G. Giannini and M. Levrero, for helpful suggestions, L. Di Magno, M. Della Guardia, C. Fragomeli and D. Mazzà for experimental support.

This work was supported by the Associazione Italiana per la Ricerca sul Cancro, Telethon Grant GGP07118, the Ministry of University and Research (FIRB and PRIN), the Ministry of Health, the

Fondazione Roma Foundation, the Mariani Foundation, the Cenci-Bolognetti Foundation and the Rome Oncogenomic Center. AUTHOR INFORMATION Author notes * Gianluca Canettieri and Lucia Di

Marcotullio: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Department of Experimental Medicine, Sapienza University, 324 viale Regina Elena, 00161, Rome, Italy

Gianluca Canettieri, Lucia Di Marcotullio, Azzura Greco, Sonia Coni, Laura Antonucci, Paola Infante, Laura Pietrosanti, Enrico De Smaele, Elisabetta Ferretti, Evelina Miele, Marianna

Pelloni, Isabella Screpanti & Alberto Gulino * Department of Biochemical Sciences, Sapienza University, 324 viale Regina Elena, 00161, Rome, Italy Alessandra Giorgi & M. Eugenià

Schinin * IRBM-Merck Research Laboratories Rome, 00040, Pomezia, Italy Paola Gallinari & Christian Steinkühler * Neuromed Institute, 86077, Pozzilli, Italy Alberto Gulino * Institute of

Biostructures and Bioimaging, CNR, 80134, Napoli, Italy Giuseppina De Simone, Emilia Maria Pedone, Luigi Vitagliano & Carlo Pedone Authors * Gianluca Canettieri View author publications

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publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS G.C. and L.D.M. designed and performed experiments, analysed data and wrote the paper; A.G., S.C.,

L.A., P.I., L.P., E.M., M.P., G.D.S., E.M.P., P.G. and A.G. performed experiments; E.D.S., E.F., C.S., L.V., C.P., M.E.S. and I.S. analysed data; A.G. designed experiments, analysed data and

wrote the paper. CORRESPONDING AUTHOR Correspondence to Alberto Gulino. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY

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Marcotullio, L., Greco, A. _et al._ Histone deacetylase and Cullin3–RENKCTD11 ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation. _Nat Cell Biol_ 12, 132–142

(2010). https://doi.org/10.1038/ncb2013 Download citation * Received: 21 October 2009 * Accepted: 07 December 2009 * Published: 17 January 2010 * Issue Date: February 2010 * DOI:

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