Roles Of HIF and 2-Oxoglutarate Dependent Enzymes in Controlling Gene Expression In Hypoxia

Abstract

Hypoxia — reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance to oxygen sensing are the 2-oxoglutarate (2-OG) dependent dioxygenases (2-OGDs). Of these, Prolyl-hydroxylases have long been recognised to control the levels and function of Hypoxia Inducible Factor (HIF), a master transcriptional regulator in hypoxia, via their hydroxylase activity. However, recent studies are revealing that dioxygenases are involved in almost all aspects of gene regulation, including chromatin organisation, transcription and translation. We highlight the relevance of HIF and 2-OG dioxyenases in the control of gene expression in response to hypoxia and their relevance to human cancers.

Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing

“…Its molecule is a heterodimer formed by one of the three hypoxia-inducible subunits, such as HIF-1α or HIF-2α or HIF-3α, and an oxygen-insensitive (constitutively expressed) subunit HIF-1β. All HIF-1 target genes contain the specific nucleotide sequence of “hypoxia-responsive element” (HRE: 5′-(A/G)CGTG-3′), to which the HIF-1 heterodimer is bound to initiate their transcription; most products of HIF-1 target genes eventually serve for the local attenuation of hypoxic stress and preservation/adaptation of the involved cells (see [ 15 , 16 , 17 ]; Figure 4 ). Importantly, both HIF-1α and HIF-2α were shown to contribute to the high resistance of hypoxic tumors to chemotherapy and radiotherapy [ 15 , 16 , 17 , 18 ].…”

“…Due to its special domain organization and a set of cofactors regulating its (in)activation, subcellular localization and degradation, HIF-1α acts as an oxygen sensor whose expression, functional activity and stability are enhanced in response to hypoxia, whereas they are decreased under normoxia. Site-specific phosphorylation, deacetylation and, also, S-nitrosation at cysteine-800 of HIF-1α, the chaperoning of HIF-1α by heat shock proteins (HSP90 and HSP70) and the interaction of HIF-1α with the cAMP response element-binding protein (CREB)-binding protein (CBP)/p300 coactivator result in the nuclear translocation of this subunit, its dimerization with HIF-1β and the binding of this heterodimer to the HRE, followed by the transcription of HIF-1 target genes ([ 15 , 16 , 17 , 19 ]; Figure 4 ). In the conditions of normoxia, α-ketoglutarate- and O 2 -dependent prolyl-4-hydroxylases (PHDs) catalyze the hydroxylation of two proline residues (P402 and P564) within the so-called “oxygen-dependent degradation domain” (ODDD) of HIF-1α; such a modification ensures the subsequent polyubiquitination and proteasomal degradation of HIF-1α through the von Hippel-Lindau (VHL)-dependent proteolysis [ 15 , 16 , 17 ].…”

“…Site-specific phosphorylation, deacetylation and, also, S-nitrosation at cysteine-800 of HIF-1α, the chaperoning of HIF-1α by heat shock proteins (HSP90 and HSP70) and the interaction of HIF-1α with the cAMP response element-binding protein (CREB)-binding protein (CBP)/p300 coactivator result in the nuclear translocation of this subunit, its dimerization with HIF-1β and the binding of this heterodimer to the HRE, followed by the transcription of HIF-1 target genes ([ 15 , 16 , 17 , 19 ]; Figure 4 ). In the conditions of normoxia, α-ketoglutarate- and O 2 -dependent prolyl-4-hydroxylases (PHDs) catalyze the hydroxylation of two proline residues (P402 and P564) within the so-called “oxygen-dependent degradation domain” (ODDD) of HIF-1α; such a modification ensures the subsequent polyubiquitination and proteasomal degradation of HIF-1α through the von Hippel-Lindau (VHL)-dependent proteolysis [ 15 , 16 , 17 ]. In parallel, asparagine-803 in HIF-1α is also hydroxylated, in an oxygen-dependent manner, by asparaginyl hydroxylase (factor inhibiting HIF-1: FIH-1), which prevents the HIF-1α–CBP/p300 interactions ([ 15 , 16 , 17 ]; Figure 4 ).…”

“…In the conditions of normoxia, α-ketoglutarate- and O 2 -dependent prolyl-4-hydroxylases (PHDs) catalyze the hydroxylation of two proline residues (P402 and P564) within the so-called “oxygen-dependent degradation domain” (ODDD) of HIF-1α; such a modification ensures the subsequent polyubiquitination and proteasomal degradation of HIF-1α through the von Hippel-Lindau (VHL)-dependent proteolysis [ 15 , 16 , 17 ]. In parallel, asparagine-803 in HIF-1α is also hydroxylated, in an oxygen-dependent manner, by asparaginyl hydroxylase (factor inhibiting HIF-1: FIH-1), which prevents the HIF-1α–CBP/p300 interactions ([ 15 , 16 , 17 ]; Figure 4 ). Thus, there is the oxygen-sensitive mechanism regulating the stability, subcellular localization and functional activity of HIF-1α.…”

“…HIF-2α has 48% amino acid homology with HIF-1α, and there is a similarity in the domain organization of their molecules [ 15 , 16 , 17 ]. Like HIF-1α, HIF-2α can form heterodimers with HIF-1β that bind to the HRE to trigger the transcription of HIF-1 target genes.…”