HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signaling
- 27 October 2008
- journal article
- Published by Informa UK Limited in Cancer Biology & Therapy
- Vol. 7 (10), 1570-1580
- https://doi.org/10.4161/cbt.7.10.6561
Abstract
Histone deacetylase 3 (HDAC3) is over-expressed 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 APCMin tumors, but was less pronounced in the tumors that over-express 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 β-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 over-expression alters the epigenetic programming of colon cancer cells to impact intracellular Wnt signaling and their sensitivity to external growth regulation by vitamin D.Keywords
This publication has 66 references indexed in Scilit:
- The E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patientsBritish Journal of Cancer, 2007
- The complex language of chromatin regulation during transcriptionNature, 2007
- Action at a distance: epigenetic silencing of large chromosomal regions in carcinogenesisHuman Molecular Genetics, 2007
- The canonical Wnt signalling pathway and its APC partner in colon cancer developmentGut, 2007
- Transforming growth factor-β in cancer and metastasisCancer and Metastasis Reviews, 2006
- Histone deacetylase 3 (HDAC3) is recruited to target promoters by PML-RARα as a component of the N-CoR co-repressor complex to repress transcription in vivoBiochemical and Biophysical Research Communications, 2006
- Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiationNature Genetics, 2004
- Sir2p and Sas2p opposingly regulate acetylation of yeast histone H4 lysine16 and spreading of heterochromatinNature Genetics, 2002
- Functional Divergence between Histone Deacetylases in Fission Yeast by Distinct Cellular Localization and In Vivo SpecificityMolecular and Cellular Biology, 2002
- Histone Deacetylase and DNA Methyltransferase in Human Prostate CancerBiochemical and Biophysical Research Communications, 2001