Carrot and stick: HIF-α engages c-Myc in hypoxic adaptation

Abstract

The past decade of research on hypoxic responses has provided a considerable understanding of how cells respond to hypoxic stress at the molecular level, thanks to the identification and molecular cloning of the hypoxia-inducible transcription factor, HIF-1a. Numerous target genes have since been identified to account for various aspects of the hypoxic response, including angiogenesis and glycolysis. Yet, fundamental questions remain regarding the mechanisms by which hypoxia controls cell proliferation, genetic instability, mitochondrial biogenesis, and oxidative respiration in cancer cells. Although the protooncoprotein c-Myc appears to be the diametrical opposite of HIF-1a in most of these processes, recent studies indicate that c-Myc is an integral part of the HIF-a-c-Myc molecular pathway in the hypoxic response. It has been shown that HIF-a engages with Myc by various mechanisms to achieve oxygen homeostasis for cell survival. This article focuses on the intricate roles of cMyc in the hypoxic response, discusses various mechanisms controlling c-Myc activity by HIF-a for the regulation of hypoxiaresponsive genes, and emphasizing the outcome of gene expression apparently dependent upon hypoxic conditions, cellular context, and gene promoter. Solid tumors tend to develop hypoxia (oxygen deprivation), which arises out of the rapid cell proliferation that outstrips the supply of oxygen from the blood vessels. Consequently, tumor hypoxia activates hypoxia-inducible factor (HIF)-1a and HIF-2a, 1,2 two of the well-characterized hypoxia-inducible transcription factors critical for tumor angiogenesis, glycolysis, and metastasis. [3][4][5] Under physiological conditions, hypoxia activates the ubiquitous HIF-1a, whereas HIF-2a expression is more tissue specific. Yet in human cancers of diverse origins, both HIF-1a and HIF-2a, referred to collectively hereinafter as HIF-a, are frequently overexpressed and activated.Hypoxia-inducible factor-a is the regulatory subunit of the HIF heterodimeric complex paired with the aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF-1b). 6 They belong to the Per-ARNT-Sim (PAS) superfamily 7 of transcription factors containing basic helix-loop-helix domains (Figure 1a). Whereas PAS domains confer target gene specificity through protein-protein interactions, 8 the oxygendependent degradation domain, unique to HIF-a, mediates oxygen-dependent proteolysis. 9 As such, despite constitutive transcription and translation of the HIF1A and EPAS1 genes (encoding HIF-1a and HIF-2a, respectively), HIF-a protein levels remain low in oxygenated conditions because of proteolysis via the ubiquitin-proteasome pathway. 9-12 HIF-a degradation requires the pVHL-containing E3 ubiquitin ligase, 13-15 which recognizes two hydroxylated proline residues of HIF-a (P402 and P564 in HIF-1a; Figure 1a). [16][17][18] HIFa is hydroxylated by three prolyl hydroxylases, EglN1, EglN2, and EglN3 (better known as PHD2, PHD1, and PHD3, respectively), which sense oxygen tension and transduce oxygen signal...

Multiple Changes Induced by Fibroblasts on Breast Cancer Cells

“…The observed increase of the glycolytic enzyme expression is concordant with the increment of c-Myc expression, which is known to activate (directly or indirectly) a number of genes related to the glycolytic pathway [31,32]. The elevated levels of anaerobic metabolism, even in the presence of oxygen, known as the "Warburg effect," is a frequent clinical syndrome in oncologic patients, an observation recognized by several authors, including our group [17,25,26], as a frequent feature of neoplastic cells both in vivo and in vitro.…”

Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1

“…Many effects of HIF-1 are therefore made at the level of gene transcription; however, the direct interactions of HIF-1with other proteins, e.g. interaction between HIF-1α and c-myc or p53, remain very important 40 . During hypoxia, the pVHL-dependent proteasomal degradation of HIF-1α does not occur.…”

From antiangiogenesis to hypoxia: current research and future directions

“…66,67 Interestingly, we and others began to show recently that HIF-1α and HIF-2α have opposing effects on DNA repair; HIF-1α inhibits, whereas HIF-2α stimulates, DNA repair. 68,69 Although how these conflicting effects between HIF-1α and HIF-2α are reconciled within tumor cells needs further investigation, our results demonstrated that HIF-1α, but not HIF-2α, is essential to hypoxic downregulation of the DNA mismatch repair genes MSH2 and MSH6 70 and the double-strand break repair gene NBN. 71 Interestingly, HIF-1α does so by a distinct mechanism that is independent of the HIF-1α-ARNT pathway but involves HIF-1α func- …”