| First Author | Giardina C | Year | 2015 |
| Journal | Cancer Prev Res (Phila) | Volume | 8 |
| Issue | 5 | Pages | 387-99 |
| PubMed ID | 25873367 | Mgi Jnum | J:317290 |
| Mgi Id | MGI:6851889 | Doi | 10.1158/1940-6207.CAPR-14-0371 |
| Citation | Giardina C, et al. (2015) Regulation of VDR Expression in Apc-Mutant Mice, Human Colon Cancers and Adenomas. Cancer Prev Res (Phila) 8(5):387-99 |
| abstractText | One variable that may affect the ability of vitamin D to reduce colon cancer risk is the expression of its high-affinity receptor, VDR. Here, we show that vitamin D does not reduce tumor formation in Apc(Delta14/+) mice and that VDR expression is lost in the majority of the colon tumor cells. The extent of VDR loss corresponded inversely to the level of beta-catenin nuclear localization and could be observed in early lesions composed of just a few crypts. Analysis of reported VDR regulators showed that the repressing class I histone deacetylases (HDAC) were significantly elevated in the tumors (up to 4-fold), whereas the VDR-activating retinoid X receptors (RXR) were downregulated ( approximately 50%). Expression of the Slug repressor was also increased, but was found primarily in stromal cells. Analysis of epigenetically active compounds on colon cell lines and intestinal organoids showed that HDAC inhibitors were particularly adept at stimulating VDR expression. Treatment of tumor-bearing Apc(Delta14/+) mice with the HDAC inhibitor panobinostat increased VDR expression in the tumors and normal mucosa. The RXR agonist bexarotene failed to activate VDR expression, indicating that RXR ligands were not limiting. Analysis of human microarray data indicated that VDR mRNA is frequently downregulated in colon adenomas, which correlated positively with RXRA expression and inversely with HDAC 2 and 8 expression. Human adenomas showed variable VDR protein expression levels, both between and within individual lesions. Determining the mechanisms of VDR regulation in colon neoplasms may significantly enhance our ability to use vitamin D as a cancer prevention agent. |
