MCB Accepts, published online ahead of print on 26 October 2009

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Mol. Cell. Biol. doi:10.1128/MCB.00444-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Regulation of the Histone Demethylase JMJD1A by HIF-1 Enhances Hypoxic Gene Expression and Tumor Growth.

Adam J. Krieg, Erinn B. Rankin, Denise Chan, Olga Razorenova, Sully Fernandez, and Amato J. Giaccia^*

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, California 94303-5152; University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

^* To whom correspondence should be addressed. Email: giaccia{at}stanford.edu.

The hypoxia-inducible transcription factors (HIFs) directly and indirectly mediate cellular adaptation to reduced oxygen tensions. Recent studies have shown that the histone demethylases JMJD1A, JMJD2B, and JARID1B are HIF targets, suggesting that HIF indirectly influences 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.