HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression

Abstract

Hypoxia-inducible factors (HIFs) are broadly expressed in human cancers, and HIF1α and HIF2α were previously suspected to promote tumour progression through largely overlapping functions. However, this relatively simple model has now been challenged in light of recent data from various approaches that reveal unique and sometimes opposing activities of these HIFα isoforms in both normal physiology and disease. These effects are mediated in part through the regulation of unique target genes, as well as through direct and indirect interactions with important oncoproteins and tumour suppressors, including MYC and p53. As HIF inhibitors are currently undergoing clinical evaluation as cancer therapeutics, a more thorough understanding of the unique roles performed by HIF1α and HIF2α in human neoplasia is warranted.

Figure 1. HIF1α and HIF2α exhibit antagonistic functions in nitric oxide (NO) production

Under low IFNy conditions, HIF2α is more abundant and induces arginase1 expression, resulting in NO production. Under high IFNy conditions, HIF2α is diminished and HIF1α dominates so that iNOS can utilize arginine for NO generation. These physiologically antagonistic functions allow the HIFα subunits to coordinately regulate NO production in a cytokine-induced and transcription-dependent fashion.

Figure 2. HIF1α and HIF2α are post-translationally modified, and differentially regulated by multiple mechanisms

(A) Multiple mechanisms differentially regulate HIF1α and HIF2α at the levels of transcription or mRNA stability (red), mRNA translation (green), and protein stability (blue). In most cases, these regulatory events have opposite effects on HIF1α and HIF2α expression, or appear to be specific for only one HIFα isoform. See text for details. (NE), no effect. (8) Summary of phosphorylations, acetylations, and hydroxylations of the two HIFα subunits by CK1, ARD1, PHDs, FIH, MAPK, SIRT1, PKD1, and ATM. It should be noted that ARD1 acetylates HIF1α, while SIRT1 deacetylates both HIF1α and HIF2α. (C) Sequence alignment of HIF2α residues 301-331 with a similar region of HIF1α; shaded residues are unique to HIF2α and allow the selective phosphorylation of HIF2α T324 by PKD1.

Figure 2. HIF1α and HIF2α are post-translationally modified, and differentially regulated by multiple mechanisms

(A) Multiple mechanisms differentially regulate HIF1α and HIF2α at the levels of transcription or mRNA stability (red), mRNA translation (green), and protein stability (blue). In most cases, these regulatory events have opposite effects on HIF1α and HIF2α expression, or appear to be specific for only one HIFα isoform. See text for details. (NE), no effect. (8) Summary of phosphorylations, acetylations, and hydroxylations of the two HIFα subunits by CK1, ARD1, PHDs, FIH, MAPK, SIRT1, PKD1, and ATM. It should be noted that ARD1 acetylates HIF1α, while SIRT1 deacetylates both HIF1α and HIF2α. (C) Sequence alignment of HIF2α residues 301-331 with a similar region of HIF1α; shaded residues are unique to HIF2α and allow the selective phosphorylation of HIF2α T324 by PKD1.

Figure 2. HIF1α and HIF2α are post-translationally modified, and differentially regulated by multiple mechanisms

(A) Multiple mechanisms differentially regulate HIF1α and HIF2α at the levels of transcription or mRNA stability (red), mRNA translation (green), and protein stability (blue). In most cases, these regulatory events have opposite effects on HIF1α and HIF2α expression, or appear to be specific for only one HIFα isoform. See text for details. (NE), no effect. (8) Summary of phosphorylations, acetylations, and hydroxylations of the two HIFα subunits by CK1, ARD1, PHDs, FIH, MAPK, SIRT1, PKD1, and ATM. It should be noted that ARD1 acetylates HIF1α, while SIRT1 deacetylates both HIF1α and HIF2α. (C) Sequence alignment of HIF2α residues 301-331 with a similar region of HIF1α; shaded residues are unique to HIF2α and allow the selective phosphorylation of HIF2α T324 by PKD1.

Figure 3. Differential regulation of HIF1α and HIF2α by SIRT1

(A) High levels of NAD⁺ inactivate SIRT1, resulting in decreased HIF1α transcriptional activity and enhanced HIF2α stimulation of target genes like erythropoietin. (8) Distinct effects of HIF1α and HIF2α on MYC complex formation and promoter occupancy. Hypoxic cells exclusively expressing HIF1α exhibit decreased MYC activity due to diminished association with MAX and SP1, as well as reduced MYC stability. HIF1α also induces MXI1 expression, which inhibits MYC target gene expression (see text for details). Cells expressing HIF2α exhibit increased MYC complex formation and target gene activation, although the mechanisms involved are not fully understood.

Figure 3. Differential regulation of HIF1α and HIF2α by SIRT1

(A) High levels of NAD⁺ inactivate SIRT1, resulting in decreased HIF1α transcriptional activity and enhanced HIF2α stimulation of target genes like erythropoietin. (8) Distinct effects of HIF1α and HIF2α on MYC complex formation and promoter occupancy. Hypoxic cells exclusively expressing HIF1α exhibit decreased MYC activity due to diminished association with MAX and SP1, as well as reduced MYC stability. HIF1α also induces MXI1 expression, which inhibits MYC target gene expression (see text for details). Cells expressing HIF2α exhibit increased MYC complex formation and target gene activation, although the mechanisms involved are not fully understood.