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

By Sully Fern and Amato J. Giaccia

Abstract

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 ad-renomedullin (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. Cellular hypoxia occurs when the demands of growth and metabolism of a tissue surpass the vascular oxygen supply. In response to hypoxia, cells undergo specific alterations in gene expression patterns geared to promote cell survival and main-tain homeostasis. This response not only is important in nor

Year: 2009
DOI identifier: 10.1128/mcb.00444-09
OAI identifier: oai:CiteSeerX.psu:10.1.1.1012.4929
Provided by: CiteSeerX
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