KDM2B controls HIF levels and activity through its JmjC and CxxC domains

Hypoxia-inducible factors (HIFs) are key regulators of cellular responses to low oxygen (hypoxia), controlling the expression of genes required for survival and adaptation. KDM2B, a chromatin-modifying enzyme, is a direct target of HIF-1α, but its precise role in regulating HIF and the hypoxia response remains unclear. Here, we investigated the role of KDM2B in the response to hypoxia in a variety of cell lines. Our analysis reveals that KDM2B depletion regulates HIF activity in a cell type dependent manner, with KDM2B depletion decreasing HIF activity in U2OS and MDA-MB-231 cells and increasing HIF activity in HeLa cells. We show that KDM2B depletion also reduces HIF-1α protein and RNA expression and reduces HIF-1α binding at hypoxia-response elements of its target genes in U2OS and MDA-MB-231 cells. Conversely, overexpression of KDM2B enhances HIF activity and HIF-1α levels in both U2OS and HEK293 cells. Mechanistically, we find that KDM2B requires its JmjC demethylase and CxxC DNA-binding domains for HIF regulation. Furthermore, we demonstrate that KDM2B is required for RNA Pol II recruitment to the promoter of HIF-1α. At the cellular level, KDM2B supports cell proliferation, with its depletion impairing proliferation and reducing cell numbers under hypoxic conditions. Our work highlights a new function of KDM2B, as a key regulator of HIF-1α expression, acting through its demethylase and DNA-binding functions. Our data indicate that KDM2B is essential for cellular adaptation to hypoxia, impacting both HIF-dependent gene expression and cell survival, and has important implications for our understanding of HIF regulation.