Regulation of the Histone Demethylase JMJD1A by Hypoxia-Inducible Factor 1α Enhances Hypoxic Gene Expression and Tumor Growth
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The hypoxia-inducible transcription factors (HIFs) directly and indirectly mediate cellular adaptation to reduced oxygen tensions. Recent studies have shown that the histone demethylase genes JMJD1A, JMJD2B, and JARID1B are HIF targets, suggesting that HIFs indirectly influence gene expression at the level of histone methylation under hypoxia. In this study, we identify a subset of hypoxia-inducible genes that are dependent on JMJD1A in both renal cell and colon carcinoma cell lines. JMJD1A regulates the expression of adrenomedullin (ADM) and growth and differentiation factor 15 (GDF15) under hypoxia by decreasing promoter histone methylation. In addition, we demonstrate that loss of JMJD1A is sufficient to reduce tumor growth in vivo, demonstrating that histone demethylation plays a significant role in modulating growth within the tumor microenvironment. Thus, hypoxic regulation of JMJD1A acts as a signal amplifier to facilitate hypoxic gene expression, ultimately enhancing tumor growth.
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Novel HIF-1-independent mechanisms regulating glycolysis under hypoxia include epigenetic reprogramming, post-translation modifications, spatial reorganization of glycolytic enzymes, and PI3K-Akt-mTOR signalling.
“Insights into novel HIF-1-independent mechanisms regulating glycolysis under hypoxia that emerged in the last decade include epigenetic reprogramming [97], post-translation modifications [98], spatial reorganization of glycolytic enzymes [98,99] and the PI3K-Akt-mTOR signalling pathway [100].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [97]
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References 59 · Cited by 334
- Authors
- Krieg, A. J., Rankin, E. B., Chan, D., Razorenova, O., Fernandez, S., & Giaccia, A. J.
- Affiliations
- Stanford Medicine (US)
- University of Pennsylvania (US)
- Corresponding author
- Krieg, Adam J.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2010-01-01
- Volume
- 30
- Issue
- 1
- Pages
- 344-353
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2798291
- OpenAlex
- W2144878837
- Cited by
- 334
- References
- 59
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 7 · 2023: 16 · 2022: 14 · 2021: 19 · 2020: 24 · 2019: 15 · 2018: 18 · 2017: 24 · 2016: 25 · 2015: 32 · 2014: 19 · 2013: 33 · 2012: 23
- FWCI
- 7.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- National Institutes of Health
- National Cancer Institute (T32CA009151, F32CA124082, R37CA088480, CA124082, R01CA088480, CA 88480, CA09151-32, T32CA121940)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- JMJD1A, histone demethylase, hypoxia-inducible factor-1α, hypoxia, histone methylation, adrenomedullin, growth and differentiation factor 15, tumor growth, renal cell carcinoma, colon cancer, tumor microenvironment, hypoxic gene expression
- MeSH terms
- Animals, Gene Expression Regulation, Histones, Humans, Male, Methylation, Neoplasm Transplantation, Neoplasms, Experimental, Promoter Regions, Genetic, Transplantation, Heterologous, Cell Hypoxia, Mice, SCID, Oligonucleotide Array Sequence Analysis, Epigenesis, Genetic, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Adrenomedullin, Growth Differentiation Factor 15, Jumonji Domain-Containing Histone Demethylases
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