Histone deacetylase and Cullin3–RENKCTD11 ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation

Canettieri, Gianluca; Marcotullio, Lucia Di; Greco, Azzura; Coni, Sonia; Antonucci, Laura; Infante, Paola; Pietrosanti, Laura; Smaele, Enrico De; Ferretti, Elisabetta; Miele, Evelina; Pelloni, Marianna; Simone, Giuseppina De; Pedone, Emilia; Gallinari, Paola; Giorgi, Alessandra; Steinkühler, Christian; Vitagliano, Luigi; Pedone, Carlo; Schinin, M Eugenià; Screpanti, Isabella; Gulino, Alberto

doi:10.1038/ncb2013

Cited by 298 publications

(399 citation statements)

References 41 publications

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“…Protein extracts preparation and immunoprecipitation assays were described elsewhere (Felli et al, 2005;Canettieri et al, 2010) and were performed using the following antibodies: antiFlag (F7425), anti-Flag (A2220), anti-Flag-HRP (A8592) and anti-HDAC1 (H3284), purchased from Sigma-Aldrich; antiAcetyl-Lysine (06-933) and anti-Acetyl-Histone H3 (06-599) were purchased from Upstate, Temecula, CA, USA; anti-HA (sc-7392), anti-HA-HRP (sc-7392), anti-Notch3 (sc-7424), anti-p300 (sc-584), anti-b-actin (sc-1616) and anti-Ub (sc-8017) were purchased from Santa-Cruz Biotechnology, SantaCruz, CA, USA.…”

Section: Protein Extracts Immunoprecipitations and Immunoblottingsmentioning

confidence: 99%

“…The corresponding bands were cut from the gel and were processed via tryptic proteolysis, after reduction and alkylation steps. The peptide mixtures were analysed by MALDI-ToF mass spectrometry and the resulting peptide mass fingerprints used to identify proteins and determine their possible post-translational modifications by Mascot search engine (Canettieri et al, 2010).…”

Section: Mass Spectrometry Analysismentioning

confidence: 99%

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Acetylation controls Notch3 stability and function in T-cell leukemia

Palermo

Checquolo²,

Giovenco

et al. 2011

Oncogene

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Section: Protein Extracts Immunoprecipitations and Immunoblottingsmentioning

confidence: 99%

Section: Mass Spectrometry Analysismentioning

confidence: 99%

Acetylation controls Notch3 stability and function in T-cell leukemia

Palermo

Checquolo²,

Giovenco

et al. 2011

Oncogene

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“…38,39 GLI1 transcriptional activity is enhanced by HDAC1-mediated deacetylation leading to enhanced cellular proliferation and transformation. 40 An E3 ubiquitin ligase complex containing Cullin3, REN, KCASH2 and KCASK3 leads to HDAC1 degradation and reverses this phenotype. 40,41 As vorinostat inhibits HDAC1, the effect of vorinostat and GLI1 knockdown on GLI1 function may be a combination of indirect GLI1 inhibition through inhibition of HDAC1 and prevention of GLI1 induction through GLI1 knockdown.…”

Section: Discussionmentioning

confidence: 99%

“…40 An E3 ubiquitin ligase complex containing Cullin3, REN, KCASH2 and KCASK3 leads to HDAC1 degradation and reverses this phenotype. 40,41 As vorinostat inhibits HDAC1, the effect of vorinostat and GLI1 knockdown on GLI1 function may be a combination of indirect GLI1 inhibition through inhibition of HDAC1 and prevention of GLI1 induction through GLI1 knockdown. Epigenetic repression of GLI1 expression occurs in part through histone methylation.…”

Section: Discussionmentioning

confidence: 99%

A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity

et al. 2016

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Vorinostat is an FDA-approved histone deacetylase inhibitor (HDACi) that has proven clinical success in some patients; however, it remains unclear why certain patients remain unresponsive to this agent and other HDACis. Constitutive STAT (signal transducer and activator of transcription) activation, overexpression of prosurvival Bcl-2 proteins and loss of HR23B have been identified as potential biomarkers of HDACi resistance; however, none have yet been used to aid the clinical utility of HDACi. Herein, we aimed to further elucidate vorinostat-resistance mechanisms through a functional genomics screen to identify novel genes that when knocked down by RNA interference (RNAi) sensitized cells to vorinostat-induced apoptosis. A synthetic lethal functional screen using a whole-genome protein-coding RNAi library was used to identify genes that when knocked down cooperated with vorinostat to induce tumor cell apoptosis in otherwise resistant cells. Through iterative screening, we identified 10 vorinostatresistance candidate genes that sensitized specifically to vorinostat. One of these vorinostat-resistance genes was GLI1, an oncogene not previously known to regulate the activity of HDACi. Treatment of vorinostat-resistant cells with the GLI1 smallmolecule inhibitor, GANT61, phenocopied the effect of GLI1 knockdown. The mechanism by which GLI1 loss of function sensitized tumor cells to vorinostat-induced apoptosis is at least in part through interactions with vorinostat to alter gene expression in a manner that favored apoptosis. Upon GLI1 knockdown and vorinostat treatment, BCL2L1 expression was repressed and overexpression of BCL2L1 inhibited GLI1-knockdown-mediated vorinostat sensitization. Taken together, we present the identification and characterization of GLI1 as a new HDACi resistance gene, providing a strong rationale for development of GLI1 inhibitors for clinical use in combination with HDACi therapy.

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“…Genetic ablation of individual ciliar transport proteins in mice confers phenotypes that are reiterative of mutations in the primary hedgehog regulatory genes. End-stage Gli transcriptional activity is also affected by acetylation or sumoylation of the Gli proteins [52,53]. Finally, Gli transcriptional function is tempered by the presence of the multifunctional SuFu protein that can bind and sequester Gli active forms in the cytoplasm or attract transcriptional corepressors to activator Gli complexes already bound to chromatin [54,55].…”

Section: Overview Of the Hedgehog Signaling Pathwaymentioning

confidence: 99%

Targeting the CB2 cannabinoid receptor in osteoporosis

Chen

Carkner

Buttyan

2011

Expert Review of Endocrinology & Metabolism

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Hedgehog is a ligand-activated signaling pathway that regulates Gli-mediated transcription. Although most noted for its role as an embryonic morphogen, hyperactive hedgehog also causes human skin and brain malignancies. The hedgehog-related gene anomalies found in these tumors are rarely found in prostate cancer. Yet surveys of human prostate tumors show concordance of high expression of hedgehog ligands and Gli2 that correlate with the potential for metastasis and therapy-resistant behavior. Likewise, prostate cancer cell lines express hedgehog target genes, and their growth and survival is affected by hedgehog/Gli inhibitors. To date, the preponderance of data supports the idea that prostate tumors benefit from a paracrine hedgehog microenvironment similar to the developing prostate. Uncertainty remains as to whether hedgehog’s influence in prostate cancer also includes aspects of tumor cell autocrine-like signaling. The recent findings that Gli proteins interact with the androgen receptor and affect its transcriptional output have helped to identify a novel pathway through which hedgehog/Gli might affect prostate tumor behavior and raises questions as to whether hedgehog signaling in prostate cancer cells is suitably measured by the expression of Gli target genes alone.

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Histone deacetylase and Cullin3–RENKCTD11 ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation

Cited by 298 publications

References 41 publications

Acetylation controls Notch3 stability and function in T-cell leukemia

Acetylation controls Notch3 stability and function in T-cell leukemia

A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity

Targeting the CB2 cannabinoid receptor in osteoporosis

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