Hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) is a direct regulator of epidermal growth factor receptor (EGFR) signaling in breast cancer

Kozlova, Nina; Wottawa, Marieke; Katschinski, Dörthe M.; Kristiansen, Glen; Kietzmann, Thomas

doi:10.18632/oncotarget.14241

Cited by 28 publications

(12 citation statements)

References 51 publications

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“…Likewise, the data on HIF‐P4H‐2 in cancers have been controversial. It has been reported to have both protective and exacerbating roles in lung and breast cancers, for example, and in HCC . The data presented here would support the former, since the Hif‐p4h‐2 gt/gt mice had less HCC, and no increase was observed in the overall incidence of cancer.…”

Section: Discussionsupporting

confidence: 75%

Systemic long‐term inactivation of hypoxia‐inducible factor prolyl 4‐hydroxylase 2 ameliorates aging‐induced changes in mice without affecting their life span

et al. 2020

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Hypoxia inactivates hypoxia‐inducible factor (HIF) prolyl 4‐hydroxylases (HIF‐P4Hs), which stabilize HIF and upregulate genes to restore tissue oxygenation. HIF‐P4Hs can also be inhibited by small molecules studied in clinical trials for renal anemia. Knowledge of systemic long‐term inactivation of HIF‐P4Hs is limited but crucial, since HIF overexpression is associated with cancers. We aimed to determine the effects of systemic genetic inhibition of the most abundant isoenzyme HIF prolyl 4‐hydroxylase‐2 (HIF‐P4H‐2)/PHD2/EglN1 on life span and tissue homeostasis in aged mice. Our data showed no difference between wild‐type and HIF‐P4H‐2‐deficient mice in the average age reached. There were several differences, however, in the primary causes of death and comorbidities, the HIF‐P4H‐2‐deficient mice having less inflammation, liver diseases, including cancer, and myocardial infarctions, and not developing anemia. No increased cancer incidence was observed due to HIF‐P4H‐2‐deficiency. These data suggest that chronic inactivation of HIF‐P4H‐2 is not harmful but rather improves the quality of life in senescence.

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Section: Discussionsupporting

confidence: 75%

Systemic long‐term inactivation of hypoxia‐inducible factor prolyl 4‐hydroxylase 2 ameliorates aging‐induced changes in mice without affecting their life span

et al. 2020

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“…Hence, targeting P4H is a potential strategy to improve the treatment of breast cancer [129]. Cui et al found that HIF-1α was involved in the transcriptional regulation of the TFPI gene, and the hypoxic microenvironment in breast tumors can induce the procoagulant status in patients with breast cancer [130]. HIF-1α may be a target for the treatment of breast cancer–related coagulation and thrombosis.…”

Section: Targeting Hypoxia and Hifs In Cancermentioning

confidence: 99%

Role of hypoxia in cancer therapy by regulating the tumor microenvironment

et al. 2019

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AimClinical resistance is a complex phenomenon in major human cancers involving multifactorial mechanisms, and hypoxia is one of the key components that affect the cellular expression program and lead to therapy resistance. The present study aimed to summarize the role of hypoxia in cancer therapy by regulating the tumor microenvironment (TME) and to highlight the potential of hypoxia-targeted therapy.MethodsRelevant published studies were retrieved from PubMed, Web of Science, and Embase using keywords such as hypoxia, cancer therapy, resistance, TME, cancer, apoptosis, DNA damage, autophagy, p53, and other similar terms.ResultsRecent studies have shown that hypoxia is associated with poor prognosis in patients by regulating the TME. It confers resistance to conventional therapies through a number of signaling pathways in apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux.ConclusionHypoxia targeting might be relevant to overcome hypoxia-associated resistance in cancer treatment.

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“…Nonetheless, the authors claimed that EGFR downregulation was independent of the influence of HIF1α or HIF2α [136]. The pro-oncogenic adaptor protein, CIN85 has been recently identified as an indirect regulator of PHD2 activity.…”

Section: The Phd-hif Axis As a Central Regulator Of Tumor Developmentmentioning

confidence: 99%

Hif-Prolyl Hydroxylase Domain Proteins (Phds) in Cancer – Potential Targets for Anti-Tumor Therapy?

Gaete¹,

Rodríguez²,

Watts³

et al. 2020

Preprint

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Solid tumors are typically associated with unbridled proliferation of malignant cells, accompanied by an immature and dysfunctional tumor-associated vascular network. Consequent impairment in transport of nutrients and oxygen eventually leads to a hypoxic environment wherein cells must adapt to survive and overcome these stresses. Hypoxia inducible factors (HIFs) are central transcription factors in the hypoxia response and drive the expression of a vast number of survival genes in cancer cells and in cells in the tumor microenvironment. HIFs are tightly controlled by a class of oxygen sensors, the HIF-prolyl hydroxylase domain proteins (PHDs), which hydroxylate HIFs, thereby marking them for proteasomal degradation. Remarkable and intense research during the past decade has revealed that, contrary to expectations, PHDs are often overexpressed in many tumor types and that inhibition of PHDs can lead to decreased tumor growth, impaired metastasis and diminished tumor-associated immune-tolerance. Therefore, PHDs represent an attractive therapeutic target in cancer research. Multiple PHD inhibitors have been developed that have either been recently accepted in China as erythropoiesis stimulating agents (ESA) or are currently in phase III trials. We review here the function of HIFs and PHDs in cancer and related therapeutic opportunities.

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Hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) is a direct regulator of epidermal growth factor receptor (EGFR) signaling in breast cancer

Cited by 28 publications

References 51 publications

Systemic long‐term inactivation of hypoxia‐inducible factor prolyl 4‐hydroxylase 2 ameliorates aging‐induced changes in mice without affecting their life span

Systemic long‐term inactivation of hypoxia‐inducible factor prolyl 4‐hydroxylase 2 ameliorates aging‐induced changes in mice without affecting their life span

Role of hypoxia in cancer therapy by regulating the tumor microenvironment

Hif-Prolyl Hydroxylase Domain Proteins (Phds) in Cancer – Potential Targets for Anti-Tumor Therapy?

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