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Cells. 2017 Mar 17;6(1). pii: E8. doi: 10.3390/cells6010008.

KDM2 Family Members are Regulated by HIF-1 in Hypoxia.

Author information

1
Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow street, Dundee DD1 5EH, UK. m.t.batie@dundee.ac.uk.
2
Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow street, Dundee DD1 5EH, UK. j.druker@dundee.ac.uk.
3
Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow street, Dundee DD1 5EH, UK. l.dignazio@dundee.ac.uk.
4
Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow street, Dundee DD1 5EH, UK. s.rocha@dundee.ac.uk.

Abstract

Hypoxia is not only a developmental cue but also a stress and pathological stimulus in many human diseases. The response to hypoxia at the cellular level relies on the activity of the transcription factor family, hypoxia inducible factor (HIF). HIF-1 is responsible for the acute response and transactivates a variety of genes involved in cellular metabolism, cell death, and cell growth. Here, we show that hypoxia results in increased mRNA levels for human lysine (K)-specific demethylase 2 (KDM2) family members, KDM2A and KDM2B, and also for Drosophila melanogaster KDM2, a histone and protein demethylase. In human cells, KDM2 family member's mRNA levels are regulated by HIF-1 but not HIF-2 in hypoxia. Interestingly, only KDM2A protein levels are significantly induced in a HIF-1-dependent manner, while KDM2B protein changes in a cell type-dependent manner. Importantly, we demonstrate that in human cells, KDM2A regulation by hypoxia and HIF-1 occurs at the level of promoter, with HIF-1 binding to the KDM2A promoter being required for RNA polymerase II recruitment. Taken together, these results demonstrate that KDM2 is a novel HIF target that can help coordinate the cellular response to hypoxia. In addition, these results might explain why KDM2 levels are often deregulated in human cancers.

KEYWORDS:

ChIP; HIF-1; JmjC; KDM2; drosophila; hypoxia

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