The Hypoxia-Associated Factor Switches Cells from HIF-1α- to HIF-2α-Dependent Signaling Promoting Stem Cell Characteristics, Aggressive Tumor Growth and Invasion

Abstract

Most solid tumors and their metastases experience periods of low oxygen or hypoxia, which is of major clinical significance as it promotes both tumor progression and resistance to therapy. Critical mediators of the hypoxic response are the hypoxia-inducible factors HIF-1α and HIF-2α. The HIFs are nonredundant and regulate both overlapping and unique downstream target genes. Here, we describe a novel mechanism for the switch between HIF-1α– and HIF-2α–dependent transcription during tumor hypoxia caused by the hypoxia associated factor (HAF). HAF is overexpressed in a variety of tumors and its levels are decreased during acute hypoxia, but increased following prolonged hypoxia. We have previously identified HAF as an E3 ubiquitin ligase that binds and ubiquitinates HIF-1α by an oxygen and pVHL-independent mechanism, thus targeting HIF-1α for proteasomal degradation. Here, we show that HAF also binds to HIF-2α, but at a different site than HIF-1α, and increases HIF-2α transactivation without causing its degradation. HAF, thus, switches the hypoxic response of the cancer cell from HIF-1α–dependent to HIF-2α–dependent transcription and activates genes involved in invasion such as MMP9, PAI-1, and the stem cell factor OCT-3/4. The switch to HIF-2α–dependent gene expression caused by HAF also promotes an enriched tumor stem cell population, resulting in highly aggressive tumors in vivo. Thus, HAF, by causing a switch from a HIF-1α– to HIF-2α–dependent response to hypoxia, provides a mechanism for more aggressive growth of tumors under prolonged hypoxia.

cAMP-response Element-binding Protein (CREB) and NF-κB Transcription Factors Are Activated during Prolonged Hypoxia and Cooperatively Regulate the Induction of Matrix Metalloproteinase MMP1

“…8). Additionally, the prolonged hypoxic signaling induces a specific set of genes including MMP1, which may regulate changes in cell shape, migration, and invasion that are often observed during prolonged hypoxia (31). Thus, it is likely that the combinatory effect of genes regulated by CREB and NF-B as well as another transcription factor(s) determines the migratory and invasive activity of cancer cells under such condition.…”

Understanding cancer stem cell heterogeneity and plasticity

“…Recent studies, mostly via in vitro experimental manipulations ( Figure 5D), provide support to these possibilities. For example, culturing cancer cells under low O 2 tension increases the expression of 'stemness' genes and the percentage of phenotypic CSCs [127][128][129]. Experimental EMT and inflammatory cytokines IL-6, IL-8, TGFβ, and TNFα can all promote the manifestation of CSC phenotypes and properties [130][131][132][133][134][135].…”

The Role of Hypoxia-Inducible Factors in Cancer Resistance

“…Blood vessel remodeling Mouse ECS [106] NANOG pluripotency hESC [102] SOX2 pluripotency hESC [102] MMP9 invasion RCC [107] PAI-1 fibrinolysis RCC [108] , LN229 [109] uPAR invasion RCC [108] DMT-1 Iron metabolism and Lysosome Mouse intestine [110,111] …”

“…Interestingly, it has been proposed that the switch from HIF1α to HIF2α -dependent signaling plays an important role in the promotion of stemness, aggressive tumor growth, and tumor progression [80,81]. Tumor cells are subjected to a range of oxygen tensions and experience periods of acute/intermittent hypoxia or chronic/prolonged hypoxia.…”