You are not logged in.
Openly accessible

Imprinted CDKN1C is a tumor suppressor in rhabdoid tumor and activated by restoration of SMARCB1 and histone deacetylase inhibitors

Algar, Elizabeth M., Muscat, Andrea, Dagar, Vinod, Rickert, Christian, Chow, C.W., Biegel, Jaclyn A., Ekert, Paul G., Saffery, Richard, Craig, Jeff, Johnstone, Ricky W. and Ashley, David M. 2009, Imprinted CDKN1C is a tumor suppressor in rhabdoid tumor and activated by restoration of SMARCB1 and histone deacetylase inhibitors, PLoS one, vol. 4, no. 2, pp. 1-13, doi: 10.1371/journal.pone.0004482.

Attached Files
Name Description MIMEType Size Downloads
ashley-imprintedCDKN1C-2009.pdf Published version application/pdf 536.56KB 46

Title Imprinted CDKN1C is a tumor suppressor in rhabdoid tumor and activated by restoration of SMARCB1 and histone deacetylase inhibitors
Author(s) Algar, Elizabeth M.
Muscat, AndreaORCID iD for Muscat, Andrea orcid.org/0000-0003-1666-7961
Dagar, Vinod
Rickert, Christian
Chow, C.W.
Biegel, Jaclyn A.
Ekert, Paul G.
Saffery, Richard
Craig, Jeff
Johnstone, Ricky W.
Ashley, David M.
Journal name PLoS one
Volume number 4
Issue number 2
Start page 1
End page 13
Total pages 13
Publisher Public Library of Science
Place of publication San Francisco, Calif.
Publication date 2009
ISSN 1932-6203
Keyword(s) cyclin dependent kinase inhibitor 1C
DNA
histone deacetylase inhibitor
cell cycle arrest
cell proliferation
controlled study
DNA methylation
Summary SMARCB1 is deleted in rhabdoid tumor, an aggressive paediatric malignancy affecting the kidney and CNS. We hypothesized that the oncogenic pathway in rhabdoid tumors involved epigenetic silencing of key cell cycle regulators as a consequence of altered chromatin-remodelling, attributable to loss of SMARCB1, and that this hypothesis if proven could provide a biological rationale for testing epigenetic therapies in this disease. We used an inducible expression system to show that the imprinted cell cycle inhibitor CDKN1C is a downstream target for SMARCB1 and is transcriptionally activated by increased histone H3 and H4 acetylation at the promoter. We also show that CDKN1C expression induces cell cycle arrest, CDKN1C knockdown with siRNA is associated with increased proliferation, and is able to compete against the anti-proliferative effect of restored SMARCB1 expression. The histone deacetylase inhibitor (HDACi), Romidepsin, specifically restored CDKN1C expression in rhabdoid tumor cells through promoter histone H3 and H4 acetylation, recapitulating the effect of SMARCB1 on CDKNIC allelic expression, and induced cell cycle arrest in G401 and STM91-01 rhabdoid tumor cell lines. CDKN1C expression was also shown to be generally absent in clinical specimens of rhabdoid tumor, however CDKN1A and CDKN1B expression persisted. Our observations suggest that maintenance of CDKN1C expression plays a critical role in preventing rhabdoid tumor growth. Significantly, we report for the first time, parallels between the molecular pathways of SMARCB1 restoration and Romidepsin treatment, and demonstrate a biological basis for the further exploration of histone deacetylase inhibitors as relevant therapeutic reagents in the treatment of rhabdoid tumor.
Language eng
DOI 10.1371/journal.pone.0004482
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2009, Public Library of Science
Persistent URL http://hdl.handle.net/10536/DRO/DU:30052146

Document type: Journal Article
Collections: School of Medicine
Open Access Collection
Connect to link resolver
 
Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved.

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.

Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 27 times in TR Web of Science
Scopus Citation Count Cited 29 times in Scopus
Google Scholar Search Google Scholar
Access Statistics: 205 Abstract Views, 46 File Downloads  -  Detailed Statistics
Created: Mon, 29 Apr 2013, 10:45:37 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.