Document Detail


HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signaling.
MedLine Citation:
PMID:  18769117     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Histone deacetylase 3 (HDAC3) is overexpressed in approximately half of all colon adenocarcinomas. We took an RNAi approach to determine how HDAC3 influenced chromatin modifications and the expression of growth regulatory genes in colon cancer cells. A survey of histone modifications revealed that HDAC3 knockdown in SW480 cells significantly increased histone H4-K12 acetylation, a modification present during chromatin assembly that has been implicated in imprinting. This modification was found to be most prominent in proliferating cells in the intestinal crypt and in APC(Min) tumors, but was less pronounced in the tumors that overexpress HDAC3. Gene expression profiling of SW480 revealed that HDAC3 shRNA impacted the expression of genes in the Wnt and vitamin D signaling pathways. The impact of HDAC3 on Wnt signaling was complex, with both positive and negative effects observed. However, long-term knockdown of HDAC3 suppressed beta-catenin translocation from the plasma membrane to the nucleus, and increased expression of Wnt inhibitors TLE1, TLE4 and SMO. HDAC3 knockdown also enhanced expression of the TLE1 and TLE4 repressors in HT-29 and HCT116 cells. HDAC3 shRNA enhanced expression of the vitamin D receptor in SW480 and HCT116 cells, and rendered SW480 cells sensitive to 1,25-dihydroxyvitamin D3. We propose that HDAC3 overexpression alters the epigenetic programming of colon cancer cells to impact intracellular Wnt signaling and their sensitivity to external growth regulation by vitamin D.
Authors:
Cassandra A Godman; Rashmi Joshi; Brendan R Tierney; Emily Greenspan; Theodore P Rasmussen; Hsin-Wei Wang; Dong-Guk Shin; Daniel W Rosenberg; Charles Giardina
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-10-07
Journal Detail:
Title:  Cancer biology & therapy     Volume:  7     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-11-25     Completed Date:  2009-05-01     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1570-80     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Butyrates / pharmacology
Cell Line, Tumor
Colonic Neoplasms / metabolism*
Gene Expression Regulation, Neoplastic*
Histone Deacetylases / metabolism*
Humans
Immunohistochemistry / methods
Microscopy, Fluorescence / methods
Models, Biological
Proto-Oncogene Proteins c-myc / metabolism
Receptors, Calcitriol / metabolism
Signal Transduction
Vitamin D / metabolism*
Wnt Proteins / metabolism*
beta Catenin / metabolism
Grant Support
ID/Acronym/Agency:
R01 CA81428/CA/NCI NIH HHS; R21 CA125592/CA/NCI NIH HHS; R21 CA125592-01A2/CA/NCI NIH HHS; R29 CA079656/CA/NCI NIH HHS; R29 CA079656-05/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Butyrates; 0/Proto-Oncogene Proteins c-myc; 0/Receptors, Calcitriol; 0/Wnt Proteins; 0/beta Catenin; 1406-16-2/Vitamin D; EC 3.5.1.98/Histone Deacetylases; EC 3.5.1.98/histone deacetylase 3
Comments/Corrections
Comment In:
Cancer Biol Ther. 2008 Oct;7(10):1581-3   [PMID:  18787408 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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