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The hypoxia-associated factor switches cells from HIF-1?- to HIF-2?-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-1? and HIF-2?. The HIFs are nonredundant and regulate both overlapping and unique downstream target genes. Here, we describe a novel mechanism for the switch between HIF-1?- and HIF-2?-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-1? by an oxygen and pVHL-independent mechanism, thus targeting HIF-1? for proteasomal degradation. Here, we show that HAF also binds to HIF-2?, but at a different site than HIF-1?, and increases HIF-2? transactivation without causing its degradation. HAF, thus, switches the hypoxic response of the cancer cell from HIF-1?-dependent to HIF-2?-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-2?-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-1?- to HIF-2?-dependent response to hypoxia, provides a mechanism for more aggressive growth of tumors under prolonged hypoxia.

SUBMITTER: Koh MY

PROVIDER: S-EPMC3268651 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion.

Koh Mei Yee MY Lemos Robert R Liu Xiuping X Powis Garth G

Cancer research 20110421 11

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 ...[more]

PMID: 21512133

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Project description:BackgroundChronic hypoxia and skeletal muscle atrophy commonly coexist in patients with COPD and CHF, yet the underlying physio-pathological mechanisms remain elusive. Muscle regeneration, driven by muscle stem cells (MuSCs), holds therapeutic potential for mitigating muscle atrophy. This study endeavours to investigate the influence of chronic hypoxia on muscle regeneration, unravel key molecular mechanisms, and explore potential therapeutic interventions.MethodsExperimental mice were exposed to prolonged normobaric hypoxic air (15% pO2, 1 atm, 2 weeks) to establish a chronic hypoxia model. The impact of chronic hypoxia on body composition, muscle mass, muscle strength, and the expression levels of hypoxia-inducible factors HIF-1α and HIF-2α in MuSC was examined. The influence of chronic hypoxia on muscle regeneration, MuSC proliferation, and the recovery of muscle mass and strength following cardiotoxin-induced injury were assessed. The muscle regeneration capacities under chronic hypoxia were compared between wildtype mice, MuSC-specific HIF-2α knockout mice, and mice treated with HIF-2α inhibitor PT2385, and angiotensin converting enzyme (ACE) inhibitor lisinopril. Transcriptomic analysis was performed to identify hypoxia- and HIF-2α-dependent molecular mechanisms. Statistical significance was determined using analysis of variance (ANOVA) and Mann-Whitney U tests.ResultsChronic hypoxia led to limb muscle atrophy (EDL: 17.7%, P < 0.001; Soleus: 11.5% reduction in weight, P < 0.001) and weakness (10.0% reduction in peak-isometric torque, P < 0.001), along with impaired muscle regeneration characterized by diminished myofibre cross-sectional areas, increased fibrosis (P < 0.001), and incomplete strength recovery (92.3% of pre-injury levels, P < 0.05). HIF-2α stabilization in MuSC under chronic hypoxia hindered MuSC proliferation (26.1% reduction of MuSC at 10 dpi, P < 0.01). HIF-2α ablation in MuSC mitigated the adverse effects of chronic hypoxia on muscle regeneration and MuSC proliferation (30.9% increase in MuSC numbers at 10 dpi, P < 0.01), while HIF-1α ablation did not have the same effect. HIF-2α stabilization under chronic hypoxia led to elevated local ACE, a novel direct target of HIF-2α. Notably, pharmacological interventions with PT2385 or lisinopril enhanced muscle regeneration under chronic hypoxia (PT2385: 81.3% increase, P < 0.001; lisinopril: 34.6% increase in MuSC numbers at 10 dpi, P < 0.05), suggesting their therapeutic potential for alleviating chronic hypoxia-associated muscle atrophy.ConclusionsChronic hypoxia detrimentally affects skeletal muscle regeneration by stabilizing HIF-2α in MuSC and thereby diminishing MuSC proliferation. HIF-2α increases local ACE levels in skeletal muscle, contributing to hypoxia-induced regenerative deficits. Administration of HIF-2α or ACE inhibitors may prove beneficial to ameliorate chronic hypoxia-associated muscle atrophy and weakness by improving muscle regeneration under chronic hypoxia.

Dataset Information

The hypoxia-associated factor switches cells from HIF-1?- to HIF-2?-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion.

Publications

The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion.

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