Journal
NEOPLASIA
Volume 13, Issue 4, Pages 374-U223Publisher
ELSEVIER SCIENCE INC
DOI: 10.1593/neo.101630
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Funding
- Associazione Italiana Ricerca Cancro
- Telethon [GGP07118]
- MIUR
- Ministry of Health, Fondazione Roma
- Fondazione Mariani
- EU
- Italian Institute of Technology
- Agenzia Spaziale Italiana
- Pasteur Institute
- Cenci Bolognetti Foundation
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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 RENKCTD11 acts through ubiquitination-dependent degradation of HDAC1, thereby affecting Hh activity and medulloblastoma growth. We identify and characterize here two RENKCTD11 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 RENKCTD11 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.
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