title: Identification and characterization of KCASH2 and KCASH3, 2 novel Cullin3 adaptors suppressing histone deacetylase and Hedgehog activity in medulloblastoma.
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.
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: De Smaele
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
authors.forename: Marta
authors.initials: M
authors.lastname: Moretti
authors.forename: Marianna
authors.initials: M
authors.lastname: Pelloni
authors.forename: Maria Anna
authors.initials: MA
authors.lastname: Occhione
authors.forename: Paola
authors.initials: P
authors.lastname: Infante
authors.forename: Danilo
authors.initials: D
authors.lastname: Cucchi
authors.forename: Azzura
authors.initials: A
authors.lastname: Greco
authors.forename: Laura
authors.initials: L
authors.lastname: Pietrosanti
authors.forename: Jelena
authors.initials: J
authors.lastname: Todorovic
authors.forename: Sonia
authors.initials: S
authors.lastname: Coni
authors.forename: Gianluca
authors.initials: G
authors.lastname: Canettieri
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.forename: Roberto
authors.initials: R
authors.lastname: Bei
authors.forename: Marella
authors.initials: M
authors.lastname: Maroder
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003001:Cloning, Molecular; D044842:Cullin Proteins / Q000378:metabolism; D005260:Female; D005865:Gestational Age; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008954:Models, Biological; D015221:Potassium Channels / Q000737:chemistry; D011247:Pregnancy; D017386:Sequence Homology, Amino Acid; D014166:Transferases; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C503645:CUL3 protein, human; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D053823:Hedgehog Proteins; D056572:Histone Deacetylase Inhibitors; C559191:KCTD21 protein, human; C559190:KCTD6 proetin, human; D015221:Potassium Channels; C488725:KCTD11 protein, human; D014166:Transferases; D006655:Histone Deacetylases