title: 1alpha,25-Dihydroxyvitamin D3 inhibits transcriptional potential of nuclear factor kappa B in breast cancer cells.
abstract: 1alpha,25-Dihydroxyvitamin D(3) (VD(3)), 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-kappaB). Previous studies indicated that VD(3) can either activate or inhibit NF-kappaB via Akt-induced I kappaB alpha phosphorylation and increase in I kappaB alpha synthesis respectively. At present, the relevant contribution of each mechanism has not been fully explored. We observed a VD(3)-mediated NF-kappaB inhibitory effect in vitamin D receptor (VDR)-positive MCF-7 breast cancer cells. We showed that VD(3) induced VDR-dependent I kappaB alpha expression but still able to lead on transient NF-kappaB p65 nuclear translocation through Akt-induced I kappaB alpha phosphorylation. Upon TNFalpha stimulation, VD(3) was not capable to inhibit I kappaB alpha degradation, p65 nuclear translocation and p65/p50-DNA binding. Here, we found that VD(3) strongly repressed p65 transactivation in MCF-7 cells using Gal4-p65 chimeras system. VDR was required for the VD(3)-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 VD(3)-induced p65 transrepression. In addition, knockdown of two nuclear corepressors HDAC3 and SMRT relieved p65 transactivation and particular TNFalpha-triggered gene expression. In conclusion, the reduction of gene activation by VD(3) in breast cancer cells was caused by the interference of the transactivation potential of NF-kappaB p65 subunit. Our studies provide a scientific background for rational use of vitamin D in the prevention and treatment of inflammatory diseases.
authors.affiliation: Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China.
authors.forename: Anfernee Kai-Wing
authors.initials: AK
authors.lastname: Tse
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Zhu
authors.forename: Chi-Keung
authors.initials: CK
authors.lastname: Wan
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Shen
authors.forename: Zhi-Ling
authors.initials: ZL
authors.lastname: Yu
authors.forename: Wang-Fun
authors.initials: WF
authors.lastname: Fong
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D002117:Calcitriol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology; D000099186:Histone Deacetylase 3
chemical_list: D002117:Calcitriol; D006655:Histone Deacetylases; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D056985:Nuclear Receptor Co-Repressor 2; D018167:Receptors, Calcitriol; D014409:Tumor Necrosis Factor-alpha; D014815:Vitamins; D000099186:Histone Deacetylase 3; C539130:NCOR2 protein, human; C000606204:NFKBIA protein, human