Journal
HUMAN MOLECULAR GENETICS
Volume 20, Issue 23, Pages 4655-4665Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddr399
Keywords
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Funding
- Ministerio de Ciencia e Innovacion of Spain [SAF2010-18302, SAF2010-20750]
- Fondo Europeo de Desarrollo Regional-Instituto de Salud Carlos III [RD06/0020/0009, RD06/0020/0020]
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KDM6B/JMJD3 is a histone H3 lysine demethylase with an important gene regulatory role in development and physiology. Here, we show that human JMJD3 expression is induced by the active vitamin D metabolite 1 alpha,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) and that JMJD3 modulates the gene regulatory action of this hormone. 1,25(OH)(2)D-3 activates the JMJD3 gene promoter and increases the level of JMJD3 RNA in human cancer cells. JMJD3 upregulation was strictly dependent on vitamin D receptor (VDR) expression and was abolished by cycloheximide. In SW480-ADH colon cancer cells, JMJD3 knockdown or expression of an inactive mutant JMJD3 fragment decreased the induction by 1,25(OH)(2)D-3 of several target genes and of an epithelial adhesive phenotype. Moreover, JMJD3 knockdown upregulated the epithelial-to-mesenchymal transition inducers SNAIL1 and ZEB1 and the mesenchymal markers fibronectin and LEF1, while it downregulated the epithelial proteins E-cadherin, Claudin-1 and Claudin-7. Additionally, JMJD3 knockdown abolished the nuclear export of beta-catenin and the inhibition of beta-catenin transcriptional activity caused by 1,25(OH)(2)D-3. Importantly, the expression of JMJD3 correlated directly with that of VDR and inversely with that of SNAI1 in a series of 96 human colon tumours. Our results indicate for the first time that an epigenetic gene coding for a histone demethylase such as JMJD3 is a VDR co-target that partially mediates the effects of 1,25(OH)(2)D-3 on human colon.
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