HIF1α stabilization in hypoxia is not oxidant-initiated.
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ABSTRACT:
SUBMITTER: Kumar A
PROVIDER: S-EPMC8530508 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cellular adaptation to low oxygen tension triggers primitive pathways that ensure proper cell function. Conditions of hypoxia and low glucose are characteristic of injured tissues and hence successive waves of inflammatory cells must be suited to function under low oxygen tension and metabolic stress. While Hypoxia-Inducible Factor (HIF)-1α has been shown to be essential for the inflammatory response of myeloid cells by regulating the metabolic switch to glycolysis, less is known about how HIF1α is triggered in inflammation. Here, we demonstrate that cells of the innate immune system require activity of the inositol-requiring enzyme 1α (IRE1α/XBP1) axis in order to initiate HIF1α-dependent production of cytokines such as IL1β, IL6 and VEGF-A. Knockout of either HIF1α or IRE1α in myeloid cells ameliorates vascular phenotypes in a model of retinal pathological angiogenesis driven by sterile inflammation. Thus, pathways associated with ER stress, in partnership with HIF1α, may co-regulate immune adaptation to low oxygen.
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Project description:Hypoxia through transcription factor HIF1α plays a critical role in cancer development. In prostate cancer, HIF1α interplays with androgen receptor (AR) to contribute to the progression of this disease to its lethal form-castration-resistant prostate cancer (CRPC). Hypoxia upregulates several epigenetic factors including histone demethylase KDM3A which is a critical co-factor of HIF1α. However, how histone demethylases regulate hypoxia signaling is not fully understood. Here, we report that histone demethylase PHF8 plays an essential role in hypoxia signaling. Knockdown or knockout of PHF8 by RNAi or CRISPR-Cas9 system reduced the activation of HIF1α and the induction of HIF1α target genes including KDM3A. Mechanistically, PHF8 regulates hypoxia inducible genes mainly through sustaining the level of trimethylated histone 3 lysine 4 (H3K4me3), an active mark in transcriptional regulation. The positive role of PHF8 in hypoxia signaling extended to hypoxia-induced neuroendocrine differentiation (NED), wherein PHF8 cooperates with KDM3A to regulate the expression of NED genes. Moreover, we discovered that the role of PHF8 in hypoxia signaling is associated with the presence of full-length AR in CRPC cells. Collectively, our study identified PHF8 as a novel epigenetic factor in hypoxia signaling, and the underlying regulatory mechanisms likely apply to general cancer development involving HIF1α. Therefore, targeting PHF8 can potentially be a novel therapeutic strategy in cancer therapy.
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Project description:Uncovering the mechanisms that underpin how tumor cells adapt to microenvironmental stress is essential to better understand cancer progression. The HACE1 (HECT domain and ankyrin repeat-containing E3 ubiquitin-protein ligase) gene is a tumor suppressor that inhibits the growth, invasive capacity, and metastasis of cancer cells. However, the direct regulatory pathways whereby HACE1 confers this tumor-suppressive effect remain to be fully elucidated. In this report, we establish a link between HACE1 and the major stress factor, hypoxia-inducible factor 1 alpha (HIF1α). We find that HACE1 blocks the accumulation of HIF1α during cellular hypoxia through decreased protein stability. This property is dependent on HACE1 E3 ligase activity and loss of Ras-related C3 botulinum toxin substrate 1 (RAC1), an established target of HACE1 mediated ubiquitinylation and degradation. In vivo, genetic deletion of Rac1 reversed the increased HIF1α expression observed in Hace1-/- mice in murine KRasG12D-driven lung tumors. An inverse relationship was observed between HACE1 and HIF1α levels in tumors compared to patient-matched normal kidney tissues, highlighting the potential pathophysiological significance of our findings. Together, our data uncover a previously unrecognized function for the HACE1 tumor suppressor in blocking HIF1α accumulation under hypoxia in a RAC1-dependent manner.
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Project description:Hypoxic pulmonary hypertension (PH) is a progressive disease characterized by hyper-proliferation of pulmonary vascular cells including pulmonary artery smooth muscle cells (PASMCs) and can lead to right heart failure and early death. Selective degradation of mitochondria by mitophagy during hypoxia regulates mitochondrial functions in many cells, however, it is not clear if mitophagy is involved in the pathogenesis of hypoxic PH. By employing the hypoxic mitophagy receptor Fundc1 knockout (KO) and transgenic (TG) mouse models, combined hypoxic PH models, the current study found that mitophagy is actively involved in hypoxic PH through regulating PASMC proliferation. In the pulmonary artery medium from hypoxic PH mice, mitophagy was upregulated, accompanied with the increased active form of FUNDC1 protein and the enhanced binding affinity of FUNDC1 with LC3B. In PASMCs, overexpression of FUNDC1 increased mitophagy and cell proliferation while knockdown of FUNDC1 inhibited hypoxia-induced mitophagy and PASMC proliferation. Stimulation of mitophagy by FUNDC1 in PASMCs elevated ROS production and inhibited ubiquitination of hypoxia inducible factor 1α (HIF1α), and inhibition of mitophagy by FUNDC1 knockdown or knockout abolished hypoxia-induced ROS-HIF1α upregulation. Moreover, Fundc1 TG mice developed severe hemodynamics changes and pulmonary vascular remodeling, and Fundc1 KO mice were much resistant to hypoxic PH. In addition, intraperitoneal injection of a specific FUNDC1 peptide inhibitor to block mitophagy ameliorated hypoxic PH. Our results reveal that during hypoxic PH, FUNDC1-mediated mitophagy is upregulated which activates ROS-HIF1α pathway and promotes PASMC proliferation, ultimately leads to pulmonary vascular remodeling and PH.
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Project description:Hypoxia inducible factor 1α (HIF1α) is a master regulator leading to metabolic adaptation, an essential physiological process to maintain the survival of stem cells under hypoxia. However, it is poorly understood how HIF1α translocates into the nucleus in stem cells under hypoxia. Here, we investigated the role of a motor adaptor protein Bicaudal D homolog 1 (BICD1) in dynein-mediated HIF1α nuclear translocation and the effect of BICD1 regulation on hypoxia adaptation and its therapeutic potential on human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs). In our results, silencing of BICD1 but not BICD2 abolished HIF1α nuclear translocation and its activity. BICD1 overexpression further enhanced hypoxia-induced HIF1α nuclear translocation. Hypoxia stimulated direct bindings of HIF1α to BICD1 and the intermediate chain of dynein (Dynein IC), which was abolished by BICD1 silencing. Akt inhibition reduced the binding of BICD1 to HIF1α and nuclear translocation of HIF1α. Conversely, Akt activation or GSK3β silencing further enhanced the hypoxia-induced HIF1α nuclear translocation. Furthermore, BICD1 silencing abolished hypoxia-induced glycolytic reprogramming and increased mitochondrial ROS accumulation and apoptosis in UCB-MSCs under hypoxia. In the mouse skin wound healing model, the transplanted cell survival and skin wound healing capacities of hypoxia-pretreated UCB-MSCs were reduced by BICD1 silencing and further increased by GSK3β silencing. In conclusion, we demonstrated that BICD1-induced HIF1α nuclear translocation is critical for hypoxia adaptation, which determines the regenerative potential of UCB-MSCs.
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Project description:Obesity is associated with the accumulation of dysfunctional adipose tissue that secretes several pro-inflammatory cytokines (adipocytokines). Recent studies have presented evidence that adipose tissues in obese individuals and animal models are hypoxic, which may result in upregulation and stabilization of the hypoxia inducible factor HIF1α. Epigenetic mechanisms such as DNA methylation enable the body to respond to microenvironmental changes such as hypoxia and may represent a mechanistic link between obesity-associated hypoxia and upregulated inflammatory adipocytokines. The purpose of this study was to investigate the role of hypoxia in modifying adipocytokine DNA methylation and subsequently adipocytokine expression. We suggested that this mechanism is mediated via the DNA demethylase, ten-eleven translocation-1 (TET1), transcription of which has been shown to be induced by HIF1α. To this end, we studied the effect of hypoxia (2% O2) in differentiated subcutaneous human adipocytes in the presence or absence of HIF1α stabilizer (Dimethyloxalylglycine (DMOG), 500 μM), HIF1α inhibitor (methyl 3-[[2-[4-(2-adamantyl) phenoxy] acetyl] amino]-4-hydroxybenzoate, 30 μM), or TET1-specific siRNA. Subjecting the adipocytes to hypoxia significantly induced HIF1α and TET1 protein levels. Moreover, hypoxia induced global hydroxymethylation, reduced adipocytokine DNA promoter methylation, and induced adipocytokine expression. These effects were abolished by either HIF1α inhibitor or TET1 gene silencing. The major hypoxia-responsive adipocytokines were leptin, interleukin-1 (IL6), IL1β, tumor necrosis factor α (TNFα), and interferon γ (IFNγ). Overall, these data demonstrate an activation of the hydroxymethylation pathway mediated by TET1. This pathway contributes to promoter hypomethylation and gene upregulation of the inflammatory adipocytokines in adipocytes in response to hypoxia.
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Project description:STAT3 and HIF1α are two fundamental transcription factors involved in many merging processes, like angiogenesis, metabolism, and cell differentiation. Notably, under pathological conditions, the two factors have been shown to interact genetically, but both the molecular mechanisms underlying such interactions and their relevance under physiological conditions remain unclear. In mouse embryonic stem cells (ESCs) we manage to determine the specific subset of hypoxia-induced genes that need STAT3 to be properly transcribed and, among them, fundamental genes like Vegfa, Hk1, Hk2, Pfkp and Hilpda are worth mentioning. Unexpectedly, we also demonstrated that the absence of STAT3 does not affect the expression of Hif1α mRNA nor the stabilization of HIF1α protein, but the STAT3-driven regulation of the hypoxia-dependent subset of gene could rely on the physical interaction between STAT3 and HIF1α. To further elucidate the physiological roles of this STAT3 non-canonical nuclear activity, we used a CRISPR/Cas9 zebrafish stat3 knock-out line. Notably, hypoxia-related fluorescence of the hypoxia zebrafish reporter line (HRE:mCherry) cannot be induced when Stat3 is not active and, while Stat3 Y705 phosphorylation seems to have a pivotal role in this process, S727 does not affect the Stat3-dependent hypoxia response. Hypoxia is fundamental for vascularization, angiogenesis and immune cells mobilization; all processes that, surprisingly, cannot be induced by low oxygen levels when Stat3 is genetically ablated. All in all, here we report the specific STAT3/HIF1α-dependent subset of genes in vitro and, for the first time with an in vivo model, we determined some of the physiological roles of STAT3-hypoxia crosstalk.
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Project description:Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) respond to low levels of oxygen and induce re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, HIF-α stabilization becomes constitutive under normoxia. We develop a mathematical model that predicts how fluctuating oxygenation affects HIF-α stabilization and impacts net cell proliferation by balancing the base growth rate, the proliferative cost of HIF-α expression, and the mortality from not expressing HIF-α during hypoxia. We compare optimal net cell proliferation rate between facultative and constitutive HIF-α regulation in environments with different oxygen profiles. We find that that facultative HIF-α regulation promotes greater net cell proliferation than constitutive regulation with stochastic or slow periodicity in oxygenation. However, cell fitness is nearly identical for both HIF-α regulation strategies under rapid periodic oxygenation fluctuations. The model thus indicates that cells constitutively expressing HIF-α may be at a selective advantage when the cost of expression is low. In cancer, this condition is known as pseudohypoxia or the "Warburg Effect". We conclude that rapid and regular cycling of oxygenation levels selects for pseudohypoxia, and that this is consistent with the ecological theory of optimal defense.
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Project description:Hypoxia is an important characteristic of the tumor microenvironment. Tumor cells can survive and propagate under the hypoxia stress by activating a series of adaption response. Herein, we found that lysine-specific demethylase 5B (KDM5B) was upregulated in gastric cancer (GC) under hypoxia conditions. The genetic knockdown or chemical inhibition of KDM5B impaired the growth of GC cell adapted to hypoxia. Interestingly, the upregulation of KDM5B in hypoxia response was associated with the SUMOylation of KDM5B. SUMOylation stabilized KDM5B protein by reducing the competitive modification of ubiquitination. Furthermore, the protein inhibitor of activated STAT 4 (PIAS4) was determined as the SUMO E3 ligase, showing increased interaction with KDM5B under hypoxia conditions. The inhibition of KDM5B caused significant downregulation of hypoxia-inducible factor-1α (HIF-1α) protein and target genes under hypoxia. As a result, co-targeting KDM5B significantly improved the antitumor efficacy of antiangiogenic therapy in vivo. Taken together, PIAS4-mediated SUMOylation stabilized KDM5B protein by disturbing ubiquitination-dependent proteasomal degradation to overcome hypoxia stress. Targeting SUMOylation-dependent KDM5B upregulation might be considered when the antiangiogenic therapy was applied in cancer treatment.
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Project description:Deleption of USP29 significantly inhibits aerobic glycolysis, glutamine catabolism and proliferation of cancer cells. To test the underlying mechanisms, RNA-seq was performed using USP29 or control depleted SK-N-BE2 and Ramos cells.
2021-10-11 | GSE180797 | GEO