KDM4A regulates HIF-1 levels through H3K9me3.

ABSTRACT

Regions of hypoxia (low oxygen) occur in most solid tumours and cells in these areas are the most aggressive and therapy resistant. In response to decreased oxygen, extensive changes in gene expression mediated by Hypoxia-Inducible Factors (HIFs) contribute significantly to the aggressive hypoxic tumour phenotype. In addition to HIFs, multiple histone demethylases are altered in their expression and activity, providing a secondary mechanism to extend the hypoxic signalling response. In this study, we demonstrate that the levels of HIF-1α are directly controlled by the repressive chromatin mark, H3K9me3. In conditions where the histone demethylase KDM4A is depleted or inactive, H3K9me3 accumulates at the HIF-1α locus, leading to a decrease in HIF-1α mRNA and a reduction in HIF-1α stabilisation. Loss of KDM4A in hypoxic conditions leads to a decreased HIF-1α mediated transcriptional response and correlates with a reduction in the characteristics associated with tumour aggressiveness, including invasion, migration, and oxygen consumption. The contribution of KDM4A to the regulation of HIF-1α is most robust in conditions of mild hypoxia. This suggests that KDM4A can enhance the function of HIF-1α by increasing the total available protein to counteract any residual activity of prolyl hydroxylases.