Hypoxia induces trimethylated H3 lysine 4 by inhibition of JARID1A demethylase
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Abstract
Histone H3 lysine 4 (H3K4) trimethylation (H3K4me3) at the promoter region of genes has been linked to transcriptional activation. In the present study, we found that hypoxia (1% oxygen) increased H3K4me3 in both normal human bronchial epithelial Beas-2B cells and human lung carcinoma A549 cells. The increase of H3K4me3 from hypoxia was likely caused by the inhibition of H3K4 demethylating activity, as hypoxia still increased H3K4me3 in methionine-deficient medium. Furthermore, an in vitro histone demethylation assay showed that 1% oxygen decreased the activity of H3K4 demethylases in Beas-2B nuclear extracts because ambient oxygen tensions were required for the demethylation reaction to proceed. Hypoxia only minimally increased H3K4me3 in the BEAS-2B cells with knockdown of JARID1A, which is the major histone H3K4 demethylase in this cell line. However, the mRNA and protein levels of JARID1A were not affected by hypoxia. GeneChip and pathway analysis in JARID1A knockdown Beas-2B cells revealed that JARID1A regulates the expression of hundreds of genes involved in different cellular functions, including tumorigenesis. Knocking down of JARID1A increased H3K4me3 at the promoters of HMOX1 and DAF genes. Thus, these results indicate that hypoxia might target JARID1A activity, which in turn increases H3K4me3 at both the global and gene-specific levels, leading to the altered programs of gene expression and tumor progression. Cancer Res; 70(10); 4214–21. ©2010 AACR.
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Increased H3K4 and H3K9 histone methylation has been documented in cells treated with hypoxia in vitro.
“Moreover, increased H3K4 and H3K9 histone methylation has been documented in cells treated with hypoxia in vitro (Johnson et al., 2008; Tausendschön et al., 2011; Zhou et al., 2010).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Zhou et al., 2010
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- Authors
- Zhou, X., Sun, H., Chen, H., Zavadil, J., Kluz, T., Arita, A., & Costa, M.
- Affiliations
- NYU Langone Health (US)
- Authors' Affiliations: 1Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York and 2Department of Pathology, NYU Cancer Institute and Center for Health Informatics and Bioinformatics, NYU Langone Medical Center, New York, New York
- Corresponding author
- Costa, Max
- Venue
- Cancer Research
- Published
- 2010-05-12
- Volume
- 70
- Issue
- 10
- Pages
- 4214-4221
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3007597
- OpenAlex
- W2018367009
- Cited by
- 134
- References
- 36
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 7 · 2022: 2 · 2021: 11 · 2020: 14 · 2019: 7 · 2018: 11 · 2017: 14 · 2016: 8 · 2015: 16 · 2014: 6 · 2013: 11 · 2012: 10
- FWCI
- 4.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA16087, P30CA016087)
- National Institute of Environmental Health Sciences (ES-000260, ES014454, ES 005512, R01ES005512, P30ES000260, R01ES014454)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- hypoxia, H3K4 trimethylation, JARID1A, histone demethylation, lung cancer, bronchial epithelial cells, heme oxygenase-1, DAF, methionine deficiency, tumor progression
- MeSH terms
- Bronchi, Cells, Cultured, Epithelial Cells, Histones, Humans, Lung Neoplasms, Lysine, Promoter Regions, Genetic, RNA, Messenger, Blotting, Western, Biomarkers, Retinoblastoma Protein, DNA Methylation, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, RNA, Small Interfering, Chromatin Immunoprecipitation, Heme Oxygenase-1, Hypoxia-Inducible Factor 1, alpha Subunit, Retinoblastoma-Binding Protein 2
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