Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis

Rohwer, Nadine; Jumpertz, Sandra; Erdem, Merve; Egners, Antje; Warzecha, Klaudia Theresa; Fragoulis, Athanassios; Kühl, Anja A.; Kramann, Rafael; Neuß, Sabine; Rudolph, Ines; Endermann, Tobias; Zasada, Christin; Apostolova, Ivayla; Gerling, Marco; Kempa, Stefan; Hughes, Russell; Lewis, Claire E.; Brenner, Winfried; Malinowski, Maciej; Stockmann, Martin; Schomburg, Lutz; Faller, William J.; Sansom, Owen J.; Tacke, Frank; Morkel, Markus; Cramer, Thorsten

doi:10.1038/s41388-019-0816-4

Cited by 29 publications

(26 citation statements)

References 72 publications

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“…Growing evidence has revealed that the transcriptional activity of HIFs is regulated by epigenetic factors at multiple levels [ 71 , 72 ]. The stability of HIF-α subunits are the basis for biological function of HIF complexes and regulates hypoxia-related phenotypes of tumor cells in combination with other important epigenetic regulators [ 73 ]. Lots of different epigenetic factors, including enzymes that play a role in methylation and acetylation, and non-coding RNAs, are closely related to HIFs stability and transcriptional activity [ 74 ].…”

Section: Epigenetic Regulation Of Hifs Activitymentioning

confidence: 99%

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Mao

Wang

et al. 2020

J Exp Clin Cancer Res

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Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (HIFs) in response to low oxygen tensions within solid tumors. Under normoxia, HIF signaling pathway is inhibited due to HIF-α subunits degradation. However, in hypoxic conditions, HIF-α is activated and stabilized, and HIF target genes are successively activated, resulting in a series of tumour-specific activities. The activation of HIFs, including HIF-1α, HIF-2α and HIF-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect HIFs stability. Given its functions in tumors progression, HIFs have been regarded as therapeutic targets for improved treatment efficacy. Epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism. And with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. Here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or HIF pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.

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Section: Epigenetic Regulation Of Hifs Activitymentioning

confidence: 99%

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Mao

Wang

et al. 2020

J Exp Clin Cancer Res

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“…especially IBD and DSS-induced colitisand thereby to play a critical role in intestinal tumorigenesis 18,64 . important to note that our study did not address the effects of (pharmacological) stabilization of HIF-α.…”

Section: Different Research Groups Have Reported Hif-1 To Impact Entementioning

confidence: 99%

“…This is functionally linked to the intestinal luminal consumption of oxygen by the microbiota and the production of short-chain fatty acids which promote oxygen consumption by intestinal epithelial cells, ultimately resulting in HIF-1 protein stabilization 17 . HIF-1 guards intestinal barrier integrity in two major ways: (i) by supporting continuous proliferation via interaction with Wnt and Notch signaling 18,19 and (ii) by direct barrier stabilization 20,21 through securing of tight junctions 22 . While the function of HIF-1 has been extensively studied in intestinal inflammation and tumorigenesis, albeit with conflicting results 18,20,23 , the effect of HIF-1 on bacterial infections of the intestinal tract remains largely elusive.…”

Section: Introductionmentioning

confidence: 99%

“…HIF-1 guards intestinal barrier integrity in two major ways: (i) by supporting continuous proliferation via interaction with Wnt and Notch signaling 18,19 and (ii) by direct barrier stabilization 20,21 through securing of tight junctions 22 . While the function of HIF-1 has been extensively studied in intestinal inflammation and tumorigenesis, albeit with conflicting results 18,20,23 , the effect of HIF-1 on bacterial infections of the intestinal tract remains largely elusive. In an elegant study, the group of Paul Beck reported a functional significance of HIF-1 for bacteriainduced intestinal injury.…”

Section: Introductionmentioning

confidence: 99%

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Conditional deletion of HIF-1α provides new insight regarding the murine response to gastrointestinal infection with Salmonella Typhimurium

Robrahn

Dupont

Jumpertz

et al. 2021

Preprint

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The hypoxia-inducible transcription factor 1 (HIF-1) has been shown to ameliorate different bacterial infections through enhancement of microbial killing. While the impact of HIF-1 on inflammatory diseases of the gut has been studied intensively, its function in bacterial infections of the intestine remains largely elusive. With the help of a publicly available gene expression data set, we could infer significant activation of the HIF-1 transcription factor after oral infection of mice with Salmonella Typhimurium. This prompted us to apply lineage-restricted deletion of the Hif1a locus in mice to examine cell type-specific functions of HIF-1 in this model. We show hypoxia-independent induction of HIF-1 activity upon Salmonella infection in the intestinal epithelium as well as in macrophages. Surprisingly, Hif1a deletion in intestinal epithelial cells impacted neither disease outcome nor inflammatory activity. The conditional knockout of Hif1a in myeloid cells enhanced the mRNA expression of the largely pro-inflammatory chemokine Cxcl2, revealing a potentially inflammatory effect of HIF-1 deficiency in myeloid cells in the gut in vivo. Again, the disease outcome was not affected. In vitro HIF-1-deficient macrophages showed an overall impaired transcription of pro-inflammatory factors, however, Salmonella bypassed direct intracellular, bactericidal HIF-1-dependent mechanisms in a Salmonella pathogenicity island (SPI)-2 independent manner. Taken together, our data suggest that HIF-1 in intestinal epithelial and myeloid cells is either dispensable or compensable in the immune defense against Salmonella Typhimurium.

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“…Chen et al, 1999; Iyer et al, 1998) and neural crest chemotaxis in both Xenopus and chicks (Barriga et al, 2013). Hif1α also modulates Wnt signaling to direct gene expression and establishment of neural and skeletal muscle fates (Kaidi et al, 2007; Majmundar et al, 2015; Rohwer et al, 2019; Večeřa et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Hif1α is required for Wnt regulated gene expression during Xenopus tropicalis tail regeneration

Patel

Schattinger

Takayoshi

et al. 2021

Preprint

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Regeneration of complex tissues is initiated by an injury-induced stress response, eventually leading to activation of developmental signaling pathways, such as Wnt signaling. How early injury cues are interpreted and coupled to activation of these developmental signals and their targets is not well understood. Here, we show that Hif1α, a stress induced transcription factor, is required for tail regeneration in Xenopus tropicalis. We find that Hif1α is required for regeneration of differentiated axial tissues, including axons and muscle. Using RNA-sequencing, we find that Hif1α and Wnt converge on a broad set of genes required for posterior specification and differentiation, including the posterior hox genes. We further show that Hif1α is required for transcription via a Wnt-responsive element, a function that is conserved in both regeneration and early neural patterning. Our findings indicate a regulatory role for Hif1α in Wnt mediated gene expression across multiple tissue contexts.

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Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis

Cited by 29 publications

References 72 publications

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Conditional deletion of HIF-1α provides new insight regarding the murine response to gastrointestinal infection with Salmonella Typhimurium

Hif1α is required for Wnt regulated gene expression during Xenopus tropicalis tail regeneration

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