Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target

Abstract

In order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underlies the metabolic and functional changes of cancer cells. Noteworthy, HIF-1 represents a promising target for novel cancer therapeutics. In this review, we summarize the molecular mechanisms underlying the interplay between HIF-1 and energetic metabolism, with a focus on mitochondria, of hypoxic cancer cells.

Impact of Hypoxia over Human Viral Infections and Key Cellular Processes

“…HIF-1 was first described in 1992 in human hepatocellular carcinoma cells (Hep3B) and immediately characterized as a critical regulator of oxygen tension levels [ 6 ]. This transcription factor was later found to belong to the PER-ARNT-SIM (PAS) family and was then characterized as a heterodimeric DNA-binding protein complex composed of a constitutively expressed β subunit and an oxygen-dependent α subunit [ 7 , 8 ]. Three isoforms of the α subunit have been described since then, namely HIF-1α, HIF-2α, and HIF-3α, giving rise to three different proteins HIF-1, HIF-2, and HIF-3, respectively [ 9 , 10 ].…”

“…Three isoforms of the α subunit have been described since then, namely HIF-1α, HIF-2α, and HIF-3α, giving rise to three different proteins HIF-1, HIF-2, and HIF-3, respectively [ 9 , 10 ]. When the α and β subunits dimerize, the HIFα/β heterodimer becomes transcriptionally active, translocates to the nucleus, and binds to hypoxia response elements (HREs), which are DNA consensus sequences that are present in the regulatory regions of HIF-target genes [ 1 , 7 , 8 ]. It is important to note that for this to occur, the α subunit of HIF must be stabilized, which happens under hypoxic conditions.…”

“…It is important to note that for this to occur, the α subunit of HIF must be stabilized, which happens under hypoxic conditions. In this scenario, degradation of the α subunit of HIF is inhibited thanks to the obstruction of the von Hippel-Lindau-containing (pVHL-containing) ubiquitin E3 ligase complex function, which otherwise targets the α subunit for degradation [ 7 , 8 ]. Alternatively, inhibition of the factor inhibiting HIF-1 (FIH-1) can also stabilize HIF.…”

“…Under normoxic conditions (normal oxygen conditions), FIH-1, which is an asparaginyl hydroxylase, hydroxylates an asparagine residue in the C-terminal transactivation domain (C-TAD), which prevents the recruitment of transcriptional coactivators that bind to this region within HIF-1α. Notably, this process inhibits HIF-1α association with the transcriptional coactivator CBP/p300 and hence, the transcriptional activation of HIF-1α [ 7 , 8 ]. Importantly, prolyl-hydroxylase domain proteins (PHDs) hydroxylate two proline residues of HIF-1α (P 402 and P 564 ) [ 7 , 8 ].…”

“…Notably, this process inhibits HIF-1α association with the transcriptional coactivator CBP/p300 and hence, the transcriptional activation of HIF-1α [ 7 , 8 ]. Importantly, prolyl-hydroxylase domain proteins (PHDs) hydroxylate two proline residues of HIF-1α (P 402 and P 564 ) [ 7 , 8 ]. Once these residues are converted to hydroxyproline, pVHL can bind to HIF-1α, leading to its degradation [ 7 , 8 ].…”