Roles of hypoxia-inducible factor-1α (HIF-1α) versus HIF-2α in the survival of hepatocellular tumor spheroids

Menrad, Heidi; Werno, Christian; Schmid, Tobias; Copanaki, Ekaterini; Deller, Thomas; Dehne, Nathalie; Brüne, Bernhard

doi:10.1002/hep.23597

Cited by 116 publications

(113 citation statements)

References 29 publications

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“…Specifically, they showed that small interfering RNA (siRNA) for HIF-1a increases HIF-2a protein, whereas overexpression or siRNA for HIF-2a reduces and increases HIF-1a protein, respectively. This dual effect has been reproduced by others using unrelated cell types (Menrad et al, 2010), but the underlying mechanisms remain elusive. Raval et al (2005) demonstrated that the effect of HIF-2a on HIF1a protein requires HIF-2a binding to DNA, but concluded that it is indirect and likely involves reduced HIF-1a protein translation.…”

Section: Introductionmentioning

confidence: 77%

“…This effect is mediated through direct binding of HIF-a subunits to an rHRE in the HIF-1a proximal promoter. There is no reason to think that a similar mechanism does not operate in other cell types exposed to hypoxia or oncogenic signaling (Menrad et al, 2010). Supporting this, activation of HIF-1a/2a signaling in skin fibroblasts and renal proximal tubular epithelial cells by the iron chelator desferrioxamine and the 2-oxoglutarate analog dimethyloxalylglycine reduced HIF-1a mRNA effectively (Supplementary Figure S4).…”

Section: Ravalmentioning

confidence: 99%

“…Raval et al (2005) demonstrated that the effect of HIF-2a on HIF1a protein requires HIF-2a binding to DNA, but concluded that it is indirect and likely involves reduced HIF-1a protein translation. On the other hand, Menrad et al (2010) suggested that free radicals generated upon HIF-2a siRNA knockdown mediate HIF-1a induction in hepatocarcinoma cells. The increase in free radicals would be explained by a decrease in antioxidant enzymes (for example, catalase) that are normally activated by HIF-2a.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic regulation of HIF-1α in renal cancer cells involves HIF-1α/2α binding to a reverse hypoxia-response element

Wang

et al. 2011

Oncogene

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Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene underlies the majority of sporadic clear cell renal cell carcinomas (CCRCCs) and is also responsible for the hereditary VHL cancer syndrome. VHL loss of function results in constitutive stabilization of hypoxia-inducible factors (HIF-1a and HIF-2a) due to insufficient proteolysis in the presence of oxygen. This activates multiple genes relevant to tumorigenesis, allowing cells to acquire further mutations and undergo malignant transformation. However, the specific role of each HIF-a subunit in CCRCC tumorigenesis is not yet well understood. The current paradigm supports that in the first stages of CCRCC formation the stabilization of HIF-1a is dominant and this limits proliferation, but later on HIF-2a increases and this induces a more aggressive cell behavior. Understanding how this transition happens is highly relevant, as it may provide novel ways to treat these cancers. Here, we show that VHL inactivation in CCRCC cells results in HIF-1a/2a-dependent downregulation of HIF-1a mRNA through direct binding of either subunit to a reverse hypoxia-response element in the HIF-1a proximal promoter. This binding activates a series of repressive histone modification marks including histone 3 lysine 27 trimethylation (H3K27me3) to make the changes stable, and if overturned reduces CCRCC cell proliferation due to excessive HIF-1a expression level. Our findings thus help understand how HIF-a subunits influence each other and also reinforce the idea that epigenetic mechanisms are a key step of CCRCC progression.

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Section: Introductionmentioning

confidence: 77%

Section: Ravalmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epigenetic regulation of HIF-1α in renal cancer cells involves HIF-1α/2α binding to a reverse hypoxia-response element

Wang

et al. 2011

Oncogene

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“…51,52 Previous studies have shown that HIF1A contributes to autophagy regulation in hypoxia. 20,[24][25][26][27][68][69][70] The BH3 domains of BNIP3 and BNIP3L, known HIF1A targets, disrupt the BCL2-BECN1 complex, releasing more BECN1 to be involved in the autophagic process. 24 In NP cells, although the BNIP3 level was increased under hypoxia, the absence of a concomitant increase in p-BECN1 Ser93 indicated a possible lack of correlation with autophagic induction.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

et al. 2016

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Nucleus pulposus (NP) cells reside in the avascular and hypoxic microenvironment of intervertebral discs. Importantly, many activities related to survival and function of NP cells are controlled by the HIF-family of transcription factors. We hypothesize that NP cells adapt to their hypoxic niche through modulation of macroautophagy/autophagy. In various cell types, hypoxia induces autophagy in a HIF1A-dependent fashion; however, little is known about hypoxic regulation of autophagy in NP cells. Hypoxia increases the number of autophagosomes as seen by TEM analysis and LC3-positive puncta in NP cells. Hypoxic induction of autophagy was also demonstrated by a significantly higher number of autophagosomes and smaller change in autolysosomes in NP cells expressing tandem-mCherry-EGFP-LC3B. Increased LC3-II levels were not accompanied by a concomitant increase in BECN1 or the ATG12-ATG5 complex. In addition, ULK1 phosphorylation at Ser757 and Ser777 responsive to MTOR and AMPK, respectively, was not affected in hypoxia. Interestingly, when MTOR activity was inhibited by rapamycin or Torin1, LC3-II levels did not change, suggesting a novel MTOR-independent regulation. Noteworthy, while silencing of HIF1A affected hypoxic induction of BNIP3, it did not affect LC3-II levels, indicating hypoxia-induced autophagy is HIF1-independent. Importantly, there was no change in the number of LC3-positive autophagosomes in NP-specific Hif1a null mice. Finally, inhibition of autophagic flux did not affect the glycolytic metabolism of NP cells, suggesting a possible nonmetabolic role of autophagy. Taken together, our study for the first time shows that NP cells regulate autophagy in a noncanonical fashion independent of MTOR and HIF1A signaling.

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“…Hypoxia-inducible factors (HIFs), which are heterodimers composed of an α and β subunit, have been implicated in the regulation of the hypoxic response (12,13). HIF-1 was reported to mediate the expression of hundreds of genes, including those for vascular endothelial growth factors, glycolytic enzymes and glucose transporters (14,15).…”

Section: Introductionmentioning

confidence: 99%

Targeting hypoxia-inducible factor-2α enhances sorafenib antitumor activity via β-catenin/C-Myc-dependent pathways in hepatocellular carcinoma

Liu

Dong

et al. 2015

Oncology Letters

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Abstract. Sorafenib is a type of multikinase inhibitor that exhibits antiangiogenic and antiproliferative effects; in addition, sorafenib is a unique first-line drug recommended for the treatment of advanced hepatocellular carcinoma (HCC). However, the effectiveness of HCC treatment remains poor due to acquired drug resistance. It has been suggested that hypoxia, induced as a results of the antiangiogenic effects of sustained sorafenib treatment, may be an important factor in sorafenib resistance. The transcription factor hypoxia-inducible factor (HIF)-2α has been reported to be associated with cell proliferation under hypoxic conditions; therefore, it was hypothesized that hypoxia may enhance tumor cell proliferation via this mechanism. The present study aimed to evaluate whether the knock-down of HIF-2α was able to enhance the therapeutic efficacy of sorafenib in order to effectively treat HCC. The results demonstrated that hypoxia protected HCC cells against sorafenib; however, short hairpin RNA-HIF-2α transfection in combination with sorafenib treatment exhibited a significantly synergistic effect against HCC cell proliferation. In addition, HCC cells acquired increased β-catenin/C-Myc expression, which enhanced proliferation under hypoxic conditions; however, targeted knock-down of HIF-2α or C-Myc markedly decreased cell proliferation in HCC cells. In conclusion, the results of the present study indicated that the targeted knock-down of HIF-2α in combination with sorafenib may be a promising strategy for the treatment of HCC.

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Roles of hypoxia-inducible factor-1α (HIF-1α) versus HIF-2α in the survival of hepatocellular tumor spheroids

Cited by 116 publications

References 29 publications

Epigenetic regulation of HIF-1α in renal cancer cells involves HIF-1α/2α binding to a reverse hypoxia-response element

Epigenetic regulation of HIF-1α in renal cancer cells involves HIF-1α/2α binding to a reverse hypoxia-response element

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

Targeting hypoxia-inducible factor-2α enhances sorafenib antitumor activity via β-catenin/C-Myc-dependent pathways in hepatocellular carcinoma

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