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KDM6B/JMJD3 histone demethylase is induced by vitamin D and modulates its effects in colon cancer cells
Open accessAbstract
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 1α,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 β-catenin and the inhibition of β-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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“Regarding epigenetic mechanisms, vitamin D, through its interaction with the vitamin D receptor (VDR), can modulate the activity of chromatin-modifying enzymes, including DNA methyltransferases (DNMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs).”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [152]
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Metadata
- Authors
- Pereira, F., Barbáchano, A., Silva, J., Bonilla, F., Campbell, M. J., Muñoz, A., & Larriba, M. J.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Hospital Universitario Puerta de Hierro Majadahonda (ES)
- Roswell Park Comprehensive Cancer Center (US)
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-09-02
- Volume
- 20
- Issue
- 23
- Pages
- 4655-4665
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2130478754
- Cited by
- 177
- References
- 57
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 6 · 2023: 7 · 2022: 27 · 2021: 14 · 2020: 11 · 2019: 14 · 2018: 16 · 2017: 12 · 2016: 9 · 2015: 9 · 2014: 14 · 2013: 11 · 2012: 9
- FWCI
- 4.55
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Vitamin D Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- vitamin D, 1,25-dihydroxyvitamin D3, vitamin D receptor, colon cancer, epithelial-mesenchymal transition, SNAI1, ZEB1, E-cadherin, claudin-1, claudin-7, gene expression regulation, epigenetic regulation
- MeSH terms
- Snail Family Transcription Factors, Calcitriol, Colonic Neoplasms, Enzyme Induction, Humans, Transcription Factors, Vitamin D, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Receptors, Calcitriol, Cell Line, Tumor, Cell Proliferation, Gene Knockdown Techniques, Jumonji Domain-Containing Histone Demethylases, Epithelial-Mesenchymal Transition, Wnt Signaling Pathway
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