Background and Significance

Oxygen homeostasis is essential for normal development and physiology, and many pathological processes are associated with hypoxia. The rescue response of cells to hypoxia is chiefly mediated by the hypoxia-inducible factor (HIF), which can initiate the transcription of ~300 genes involved in hematopoiesis and iron metabolism, angiogenesis, glucose and lipid metabolism, inflammation and tumorigenesis. Activation of the hypoxia response pathway aims to i) increase oxygen delivery to tissues and ii) decrease its usage e.g. in oxidative metabolism. The same physiologic pathway is activated at high altitude, which is exploited by endurance athletes. HIF is an αβ dimer. The HIFα subunit isoforms HIF1α and HIF2α are synthesized constitutively, and hydroxylation of two proline residues by the HIF prolyl 4-hydroxylases (HIF-P4Hs) targets them for proteasomal degradation via the von Hippel Lindau protein (VHL) in normoxia. Under hypoxia the hydroxylation is inhibited and the accumulated HIFα forms with HIFβ a transcriptionally active dimer. HIF-P4Hs have three isoenzymes HIF-P4Hs 1-3 (also known as PHDs 1-3, and EglNs 2, 1 and 3, respectively) in vertebrates, isoenzyme 2 being the most abundant and major form in most tissues. HIF-P4Hs belong to the enzyme family of 2-oxoglutarate-dependent dioxygenases (2-OGDDs).

Epigenetic modifications to nucleic acid and protein components of the chromatin are central regulators of eukaryotic transcription. These modifications include the reversible methylation of DNA and histones, and other modifications to histones, such as acetylation, phosphorylation and ubiquitination. The epigenetic marks to chromatin are “written” or “erased” by enzymes. Several of these “erasers” are also 2-OGDDs, such as the leukemia associated DNA demethylating ten-eleven translocation (TET) enzymes and a number of JmjC-domain containing histone lysine demethylases (KDMs). KDMs play an important role in the epigenetic regulation of gene expression.

Our research group’s main interest are the HIF-P4Hs 1-3, FIH, P4H-TM, TETs and selected KDMs. The central role of HIF-P4Hs in oxygen sensing makes them promising candidates for the treatment pathologic hypoxia, such as ischemic conditions. HIF-P4Hs can be targeted with synthetic 2-OG analogue inhibitors which can be used to initiate the hypoxia response in normoxia and which can therefore be called hypoxiamimetics. We have shown recently that activating the endogenous hypoxia response pathway genetically or pharmacologically by HIF-P4H inhibition protects mice from obesity, metabolic dysfunction, high-fat diet and aging-induced hepatic steatosis and atherosclerosis. It seems possible that HIF-P4H inhibition may have protective effects also in many other disease conditions, such as hepatic, inflammatory and immunological diseases. The KDMs are currently the least studied 2-OGDD family members. KDMs regulate development, cellular differentiation, senescence and genomic stability, disruption of which can have profound effects, as evidenced by recent data indicating that several JmjC KDMs are linked to the pathogenesis of a number of cancers. We showed recently that KDMs become inhibited with low concentrations of cancer-associated 2-OG analogues and treatment of cells with these compounds altered histone demethylatiom status. Our hypothesis is that the activity of specific KDMs is dependent on oxygen availability and similarly to the HIF-P4Hs, they act as nuclear oxygen sensors, and contribute to tumorigenesis.

 

Figure. Oxygen dependent hydroxylation of HIFalfa by HIF-P4Hs.

pVHL, von Hippel Lindau protein; HRE, hypoxia response element; EPO gene for erythropoietin; VEGF, gene for vascular endothelial growth factor, GLUT-1, gene for glucose transporter-1.

 

Last updated: 17.11.2018