Abstract
Vitamin D is a fat-soluble vitamin and plays an important role in calcium absorption and bone development, whose lack can cause a variety of diseases, including cancer. Human epidemiological studies suggested that vitamin D3 deficiency might increase glioma incidence, but molecular mechanism is less understood. In this study, we show that 1,25-dihydroxyvitamin D3 (the active form of vitamin D3) induces senescence of glioma cells and increases the expression of senescence markers, INK4A and cyclin-dependent kinase inhibitor 1A (CDKN1A). 1,25-Dihydroxyvitamin D3 also upregulates the expression of histone demethylase, KDM6B. Knockdown of KDM6B attenuates 1,25-dihydroxyvitamin D3-induced senescence and upregulation of INK4A and CDKN1A. KDM6B promotes the transcription of INK4A by eliminating the trimethylation of repressive marker H3K27me3 near its promoter. This study reveals a new regulatory mechanism involved in vitamin D3 inhibition on gliomas, which is beneficial to prevention and adjuvant therapy of glioma.
Keywords:
1,25-dihydroxyvitamin D3; KDM6B; glioma; histone demethylase; senescence.
© 2019 Wiley Periodicals, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / enzymology
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Brain Neoplasms / genetics
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Brain Neoplasms / pathology
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Calcitriol / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cellular Senescence / drug effects*
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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DNA Methylation / drug effects
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Epigenesis, Genetic / drug effects
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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Glioma / drug therapy*
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Glioma / enzymology
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Glioma / genetics
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Glioma / pathology
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Humans
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Jumonji Domain-Containing Histone Demethylases / genetics
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Jumonji Domain-Containing Histone Demethylases / metabolism*
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Promoter Regions, Genetic
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Signal Transduction
Substances
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Antineoplastic Agents
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CDKN1A protein, human
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CDKN2A protein, human
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21
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Jumonji Domain-Containing Histone Demethylases
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KDM6B protein, human
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Calcitriol