Identification and characterization of KCASH2 and KCASH3, 2 novel Cullin3 adaptors suppressing histone deacetylase and Hedgehog activity in medulloblastoma.

Neoplasia 2011 Apr;13(4):374-85

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071086PMC
http://dx.doi.org/10.1593/neo.101630DOI Listing
April 2011
19 Reads

Publication Analysis

Top Keywords

medulloblastoma growth
8
activity medulloblastoma
8
histone deacetylase
8
medulloblastoma
5
expression kcash2
4
regulation putative
4
hdac regulation
4
share renkctd11
4
mechanisms hdac
4
putative tumor
4
features btb
4
transcriptional activity
4
btb domain
4
renkctd11 acts
4
suppressor renkctd11
4
novel genes
4
signaling expression
4
tumor suppressor
4
physiological mechanisms
4
kcash2 observed
4

Similar Publications