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1.
Neoplasia ; 13(4): 374-85, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21472142

ABSTRACT

Medulloblastoma is the most common pediatric malignant brain tumor, arising from aberrant cerebellar precursors' development, a process mainly controlled by Hedgehog (Hh) signaling pathway. Histone deacetylase HDAC1 has been recently shown to modulate Hh signaling, deacetylating its effectors Gli1/2 and enhancing their transcriptional activity. Therefore, HDAC may represent a potential therapeutic target for Hh-dependent tumors, but still little information is available on the physiological mechanisms of HDAC regulation. The putative tumor suppressor REN(KCTD11) acts through ubiquitination-dependent degradation of HDAC1, thereby affecting Hh activity and medulloblastoma growth. We identify and characterize here two REN(KCTD11) homologues, defining a new family of proteins named KCASH, as "KCTD containing, Cullin3 adaptor, suppressor of Hedgehog." Indeed, the novel genes (KCASH2(KCTD21) and KCASH3(KCTD6)) share with REN(KCTD11) a number of features, such as a BTB domain required for the formation of a Cullin3 ubiquitin ligase complex and HDAC1 ubiquitination and degradation capability, suppressing the acetylation-dependent Hh/Gli signaling. Expression of KCASH2 and -3 is observed in cerebellum, whereas epigenetic silencing and allelic deletion are observed in human medulloblastoma. Rescuing KCASHs expression reduces the Hedgehog-dependent medulloblastoma growth, suggesting that loss of members of this novel family of native HDAC inhibitors is crucial in sustaining Hh pathway-mediated tumorigenesis. Accordingly, they might represent a promising class of endogenous "agents" through which this pathway may be targeted.


Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Cerebellar Neoplasms/genetics , Hedgehog Proteins/antagonists & inhibitors , Medulloblastoma/genetics , Adaptor Proteins, Signal Transducing/chemistry , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adult , Aged , Aged, 80 and over , Animals , Cell Cycle Proteins , Cells, Cultured , Cerebellar Neoplasms/metabolism , Cerebellar Neoplasms/pathology , Cloning, Molecular , Cullin Proteins/metabolism , Female , Gestational Age , Hedgehog Proteins/metabolism , Histone Deacetylase Inhibitors/metabolism , Histone Deacetylases/metabolism , Humans , Medulloblastoma/metabolism , Medulloblastoma/pathology , Mice , Mice, Inbred C57BL , Middle Aged , Models, Biological , Potassium Channels/chemistry , Pregnancy , Sequence Homology, Amino Acid , Transferases , Young Adult
2.
Nat Cell Biol ; 12(2): 132-42, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20081843

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.


Subject(s)
Cullin Proteins/metabolism , Hedgehog Proteins/metabolism , Histone Deacetylases/metabolism , Nerve Tissue Proteins/metabolism , Oncogene Proteins/metabolism , Signal Transduction/physiology , Trans-Activators/metabolism , Acetylation , Animals , Cell Cycle Proteins , Cell Line , Cell Line, Tumor , Cells, Cultured , Chromatin Immunoprecipitation , Cullin Proteins/genetics , Electrophoresis, Polyacrylamide Gel , Hedgehog Proteins/genetics , Histone Deacetylase 1/genetics , Histone Deacetylase 1/metabolism , Histone Deacetylase 2/genetics , Histone Deacetylase 2/metabolism , Histone Deacetylases/genetics , 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 , Oncogene Proteins/genetics , Protein Binding , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/genetics , Spectrometry, Mass, Electrospray Ionization , Trans-Activators/genetics , Transferases , Zinc Finger Protein GLI1 , Zinc Finger Protein Gli2
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