HIF-1-Dependent Induction of Jumonji Domain-Containing Protein (JMJD) 3 under Hypoxic Conditions

Abstract

Jumonji domain-containing proteins (JMJD) catalyze the oxidative demethylation of a methylated lysine residue of histones by using O2, α-ketoglutarate, vitamin C, and Fe(II). Several JMJDs are induced by hypoxic stress to compensate their presumed reduction in catalytic activity under hypoxia. In this study, we showed that an H3K27me3 specific histone demethylase, JMJD3 was induced by hypoxia-inducible factor (HIF)-1α/β under hypoxia and that treatment with Clioquinol, a HIF-1α activator, increased JMJD3 expression even under normoxia. Chromatin immunoprecipitation (ChIP) analyses showed that both HIF-1α and its dimerization partner HIF-1β/Arnt occupied the first intron region of the mouse JMJD3 gene, whereas the HIF-1α/β heterodimer bound to the upstream region of the human JMJD3, indicating that human and mouse JMJD3 have hypoxia-responsive regulatory regions in different locations. This study shows that both mouse and human JMJD3 are induced by HIF-1.

Regulation of histone demethylase KDM6B by hypoxia-inducible factor-2α

“…While we were preparing this manuscript, another group reported similar results [37]. In that study, it was demonstrated that KDM6B is a HIF, which supports our finding.…”

“…The possible reason for the different results from the two groups may be that the cell lines used were different. Lee et al [37] used NIH-3T3 cells and mouse embryonic fibroblasts, while we used HepG2 and HEK293. Despite the interaction between KDM6B and HIF-1α in vitro, there is not obvious effect on the expression of HIF-1α target gene GLUT1 after KDM6B knockdown.…”

Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B

“…Here, we focused on the functional significance of changes in CSL levels in skin and head and neck epithelial cells. of KDM6B by NF-KB and STATs observed in other cell types (36,38,70,72,73) may also apply to squamous cancer, which is often associated with and can be induced by inflammation (74). Targeting epigenetic regulators is emerging as promising cancer therapy.…”

Hypoxic reprograming of H3K27me3 and H3K4me3 at the INK4A locus

“…Then, the qPCR analyses were performed using the indicated primer sets for the INK4A locus. The values on the y-axis are presented as the average percentage input and SD of triplicate determinations of qPCR and ChIP analyses performed as described previously [19,36] .…”