Identification and characterization of KCASH2 and KCASH3, 2 novel cullin3 adaptors suppressing histone deacetylase and hedgehog activity in medulloblastoma

Enrico de Smaele, Lucia di Marcotullio, Marta Moretti, Marianna Pelloni, Maria Anna Occhione, Paola Infante, Danilo Cucchi, Azzura Greco, Laura Pietrosanti, Jelena Todorovic, Sonia Coni, Gianluca Canettieri, Elisabetta Ferretti, Roberto Bei, Marella Maroder, Isabella Screpanti, Alberto Gulino

Research output: Contribution to journalArticlepeer-review

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 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 (KCASH2KCTD21 and KCASH3KCTD6) 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 acetylationdependent 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 Hedgehogdependent 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.

Original languageEnglish
Pages (from-to)374-385
Number of pages12
JournalNeoplasia (United States)
Volume13
Issue number4
DOIs
Publication statusPublished - Apr 2011

ASJC Scopus subject areas

  • Cancer Research

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