Regulation of the Histone Demethylase JMJD1A by Hypoxia-Inducible Factor 1α Enhances Hypoxic Gene Expression and Tumor Growth▿†

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University, Stanford, CA 94303-5152, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 10/2009; 30(1):344-53. DOI: 10.1128/MCB.00444-09
Source: PubMed


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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Available from: Olga V Razorenova, Sep 22, 2015
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    • "Furthermore, JMJD1A was shown to regulate a subset of hypoxia-induced genes, including ADM and GDF15, by maintaining a lower level of H3K9me2 at their promoter regions. JMJD1A (KDM3A) was also important for tumor growth in the hypoxic microenvironment of tumor xenografts[89]. In addition to Curr Pharmacol Rep upregulating the expression of certain demethylases, hypoxia also directly inhibits their enzyme activity because they require oxygen to carry out their enzymatic function. The compensatory upregulation of the histone demethylase expression under hypoxia and possibly with oxidative stress affords a way to identify the affected enzyme. "
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    • "The authors would like to thank Adam Krieg for generating the RCC4 VHL microarray datasets used for DAVID analysis in Figure 1B (Krieg et al. 2010). This work was funded by NIH grants CA67166 and CA116685. "
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    • "Several KDMs have now been shown to be transcriptionally up-regulated under hypoxic conditions, including KDM4B, KDM4C, and KDM6B (Krieg et al. 2010; Lee et al. 2013; Guo et al. 2015). We observed similar results in RPE cells in response to hypoxia. "
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