HIF1α stabilization in hypoxia is not oxidant-initiated

Kumar, Amit; Vaish, Manisha; Karuppagounder, Saravanan S.; Gazaryan, Irina G.; Cave, John W.; Starkov, Anatoly A.; Anderson, Elizabeth T.; Zhang, Sheng; Pinto, John T.; Rountree, Austin M.; Wang, Wang; Sweet, Ian R.; Ratan, Rajiv R.

doi:10.7554/elife.72873

Cited by 20 publications

(12 citation statements)

References 64 publications

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“…A series of elegant studies demonstrated that in hypoxia exposed cells, nitric oxide and other respiratory chain inhibitors reduce mitochondrial oxygen demand, and this leads to increases in cytosolic oxygen and subsequent increases in PHD-dependent HIF-1α degradation [ 20 – 23 ]. These studies analyzed the effects of the redistribution of oxygen on HIF-1α only, however, and therefore the question remains how this mechanism relates to HIF-2 stability.…”

Section: Introductionmentioning

confidence: 99%

The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability

et al. 2022

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The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two major HIFs, HIF-1 and HIF-2, mediate this response during prolonged hypoxia in an overlapping and sequential fashion that is referred to as the HIF switch. Both HIF proteins consist of an unstable alpha chain and a stable beta chain. The instability of the alpha chains is mediated by prolyl hydroxylase (PHD) activity during normoxic conditions, which leads to ubiquitination and proteasomal degradation of the alpha chains. During normoxic conditions, very little HIF-1 or HIF-2 alpha–beta dimers are present because of PHD activity. During hypoxia, however, PHD activity is suppressed, and HIF dimers are stable. Here we demonstrate that HIF-1 expression is maximal after 4 h of hypoxia in primary endothelial cells and then is dramatically reduced by 8 h. In contrast, HIF-2 is maximal at 8 h and remains elevated up to 24 h. There are differences in the HIF-1 and HIF-2 transcriptional profiles, and therefore understanding how the transition between them occurs is important and not clearly understood. Here we demonstrate that the HIF-1 to HIF-2 transition during prolonged hypoxia is mediated by two mechanisms: (1) the HIF-1 driven increase in the glycolytic pathways that reactivates PHD activity and (2) the much less stable mRNA levels of HIF-1α (HIF1A) compared to HIF-2α (EPAS1) mRNA. We also demonstrate that the alpha mRNA levels directly correlate to the relative alpha protein levels, and therefore to the more stable HIF-2 expression during prolonged hypoxia.

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Section: Introductionmentioning

confidence: 99%

The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability

et al. 2022

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“…S9A and S9B ). Since HIF1α is more stabilized in low oxygen concentrations or hypoxia [ 18 ], we performed this experiment in hypoxia condition. Although protein expression of HIF1α was lower after EIF4A1 heterozygous KO in DU145 cells under hypoxia, this reduction was not evident in EIF4A1 +/− PC3 cells ( Figs.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic regulation of EIF4A1 through DNA methylation and an oncogenic role of eIF4A1 through BRD2 signaling in prostate cancer

et al. 2022

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In prostate cancers, elongation initiation factor 4A1 (eIF4A1) supports an oncogenic translation program and is highly expressed, but its role remains elusive. By use of human specimens and cell models, we addressed the role of eIF4A1 in prostate cancer in vitro and in vivo . EIF4A1 expression, as determined by mRNA and protein levels, was higher in primary prostate cancers relative to normal prostate tissue. Also, for primary prostate cancers, elevated mRNA levels of EIF4A1 correlated with DNA hypomethylation levels in the CpG-rich island of EIF4A1 . Using a DNMT3a CRISPR-Cas9-based tool for specific targeting of DNA methylation, we characterized, in human prostate cancer cells, the epigenetic regulation of EIF4A1 transcripts through DNA methylation in the CpG-rich island of EIF4A1 . Next, we investigated the oncogenic effect of EIF4A1 on cancer cell proliferation in vitro and tumor growth in vivo . For prostate cancer cells, EIF4A1 heterozygous knockout or knockdown inhibited protein translation and tumor growth. In addition, using RNA immunoprecipitation with RNA sequencing, we discovered the eIF4A1-mediated translational regulation of the oncogene BRD2 , which contains the most enriched eIF4A1-binding motifs in its 5’ untranslated region, establishing an eIF4A1-BRD2 axis for oncogenic translation. Finally, we found a positive correlation between expression levels of eIF4A1 and BRD2 in primary prostate cancers. Our results demonstrate, for prostate cancer cells, epigenetic regulation of EIF4A1 transcripts through DNA methylation and an oncogenic roles of eIF4A1 through BRD2 signaling.

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“…In a hypoxic microenvironment, HIF-1α in the cytoplasm enters the nucleus and forms the HIF-1 complex with HIF-1β through the specific basic helix-loop-helix/Per-ARNT-SIM (bHLH-PAS) domain. Subsequently, HIF-1α binds to the hypoxic reaction element (HRE) in the promoter region of the HIF-1α downstream target gene by recruiting transcription activation factors, such as AMP and cap-binding protein, thus regulating the transcription of related genes ( 35 - 37 ).…”

Section: Discussionmentioning

confidence: 99%

The predictive accuracy of preoperative erythrocyte count and maximum tumor diameter to maximum kidney diameter ratio in renal cell carcinoma

Zhang¹,

Yan²,

Xu³

et al. 2022

Transl Androl Urol

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Background: The purpose of this study was to investigate the predictive accuracy of erythrocyte count and maximum tumor diameter to maximum kidney diameter ratio (TKR) in patients with renal cell carcinoma (RCC). Methods:We retrospectively analyzed the clinicopathological epidemiological characteristics of patients with RCC in the First Hospital of Shanxi Medical University from 2010 to 2014. Among them, 295 cases with complete follow-up data at the time of visit were selected. We collected data including erythrocyte counts and length of each diameter line of the tumor and kidney. To predict the prognosis of RCC, receiver operating characteristic (ROC) curve analysis was used to calculate the cutoff value of each parameter.Results: Of the 295 included patients, 199 (67.5%) were male, 96 (32.5%) were female, and the mean (± SD) age was 56.45±11.03 years. The area under the curve (AUC) of the erythrocyte count and the TKR for predicting the prognosis of RCC were 0.672 (SD 0.031; P<0.001) and 0.800 (SD 0.030; P<0.001), respectively. When the cutoff value of the erythrocyte count and TKR count were 3.975 and 0.452, the highest Youden index values were 0.309 and 0.685, and the corresponding sensitivity and specificity were 0.826 and 0.685, and 0.483 and 1.000, respectively.Conclusions: An erythrocyte count <3.975×10 12 /L and a TKR >0.452 were found to be risk factors for poor prognosis in patients with RCC.

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HIF1α stabilization in hypoxia is not oxidant-initiated

Cited by 20 publications

References 64 publications

The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability

The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability

Epigenetic regulation of EIF4A1 through DNA methylation and an oncogenic role of eIF4A1 through BRD2 signaling in prostate cancer

The predictive accuracy of preoperative erythrocyte count and maximum tumor diameter to maximum kidney diameter ratio in renal cell carcinoma

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