title: KDM2 Family Members are Regulated by HIF-1 in Hypoxia.
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.
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Batie
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow street, Dundee DD1 5EH, UK. j.druker@dundee.ac.uk.
authors.forename: Jimena
authors.initials: J
authors.lastname: Druker
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow street, Dundee DD1 5EH, UK. l.dignazio@dundee.ac.uk.
authors.forename: Laura
authors.initials: L
authors.lastname: D'Ignazio
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow street, Dundee DD1 5EH, UK. s.rocha@dundee.ac.uk.
authors.forename: Sonia
authors.initials: S
authors.lastname: Rocha
keywords: ChIP; HIF-1; JmjC; KDM2; drosophila; hypoxia