1α,25-Dihydroxyvitamin D3 inhibits transcriptional potential of nuclear factor kappa B in breast cancer cells

Anfernee K W TSE, Guo Yuan Zhu, Chi Keung Wan, Xiao Ling Shen, Zhiling YU, David W F FONG*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)

Abstract

1α,25-Dihydroxyvitamin D3 (VD3), the biologically active form of vitamin D, may have either pro- or anti-inflammatory activities because of its diverse actions on nuclear factor kappa B (NF-κB). Previous studies indicated that VD3 can either activate or inhibit NF-κB via Akt-induced IκBα phosphorylation and increase in IκBα synthesis respectively. At present, the relevant contribution of each mechanism has not been fully explored. We observed a VD3-mediated NF-κB inhibitory effect in vitamin D receptor (VDR)-positive MCF-7 breast cancer cells. We showed that VD3 induced VDR-dependent IκBα expression but still able to lead on transient NF-κB p65 nuclear translocation through Akt-induced IκBα phosphorylation. Upon TNFα stimulation, VD3 was not capable to inhibit IκBα degradation, p65 nuclear translocation and p65/p50-DNA binding. Here, we found that VD3 strongly repressed p65 transactivation in MCF-7 cells using Gal4-p65 chimeras system. VDR was required for the VD3-mediated transrepression and mutations in VDR affected its suppressive ability. We also demonstrated that neither inhibition of p65 phosphorylation nor acetylation was responsible for the transrepression. In fact, we found that treatment of MCF-7 cells with histone deacetylase inhibitors abrogated VD3-induced p65 transrepression. In addition, knockdown of two nuclear corepressors HDAC3 and SMRT relieved p65 transactivation and particular TNFα-triggered gene expression. In conclusion, the reduction of gene activation by VD3 in breast cancer cells was caused by the interference of the transactivation potential of NF-κB p65 subunit. Our studies provide a scientific background for rational use of vitamin D in the prevention and treatment of inflammatory diseases.

Original languageEnglish
Pages (from-to)1728-1738
Number of pages11
JournalMolecular Immunology
Volume47
Issue number9
DOIs
Publication statusPublished - May 2010

Scopus Subject Areas

  • Immunology
  • Molecular Biology

User-Defined Keywords

  • Cytokines
  • Inflammation
  • NF-kappaB
  • Vitamin D3

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