Solid tumours are exposed to microenvironmental factors such as hypoxia that normally inhibit cell growth. However, tumour cells are capable of counteracting these signals through mechanisms that are largely unknown. Here we show that the prolyl hydroxylase PHD3 restrains tumour growth in response to microenvironmental cues through the control of EGFR. PHD3 silencing in human gliomas or genetic deletion in a murine high-grade astrocytoma model markedly promotes tumour growth and the ability of tumours to continue growing under unfavourable conditions. The growth-suppressive function of PHD3 is independent of the established PHD3 targets HIF and NF-κB and its hydroxylase activity. Instead, loss of PHD3 results in hyperphosphorylation of epidermal growth factor receptor (EGFR). Importantly, epigenetic/genetic silencing of PHD3 preferentially occurs in gliomas without EGFR amplification. Our findings reveal that PHD3 inactivation provides an alternative route of EGFR activation through which tumour cells sustain proliferative signalling even under conditions of limited oxygen availability.
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http://dx.doi.org/10.1038/ncomms6582 | DOI Listing |
Glia
August 2023
Experimental and Clinical Research Center (ECRC), Charité-Universitätsmedizin Berlin und Max Delbrück Center or Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Astrocytes constitute the parenchymal border of the blood-brain barrier (BBB), modulate the exchange of soluble and cellular elements, and are essential for neuronal metabolic support. Thus, astrocytes critically influence neuronal network integrity. In hypoxia, astrocytes upregulate a transcriptional program that has been shown to boost neuroprotection in several models of neurological diseases.
View Article and Find Full Text PDFLife (Basel)
December 2022
Musculoskeletal Disease Center, Loma Linda VA Healthcare System, Loma Linda, CA 92357, USA.
The critical importance of hypoxia-inducible factor (HIF)s in the regulation of endochondral bone formation is now well established. HIF protein levels are closely regulated by the prolyl hydroxylase domain-containing protein (PHD) mediated ubiquitin-proteasomal degradation pathway. Of the three PHD family members expressed in bone, we previously showed that mice with conditional disruption of the Phd2 gene in chondrocytes led to a massive increase in the trabecular bone mass of the long bones.
View Article and Find Full Text PDFCell Rep
October 2021
Department of Medicine, Section of Athero & Lipo, Baylor College of Medicine, Houston, TX 77030, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:
Cardiac metabolism is a high-oxygen-consuming process, showing a preference for long-chain fatty acid (LCFA) as the fuel source under physiological conditions. However, a metabolic switch (favoring glucose instead of LCFA) is commonly reported in ischemic or late-stage failing hearts. The mechanism regulating this metabolic switch remains poorly understood.
View Article and Find Full Text PDFCells
August 2021
Musculoskeletal Disease Center, Jerry L. Pettis VA Medical Center, Loma Linda, CA 92357, USA.
We previously showed that conditional disruption of the gene in chondrocytes led to a massive increase in long bone trabecular bone mass. Loss of gene expression or inhibition of PHD2 activity by a specific inhibitor resulted in a several-fold compensatory increase in expression in chondrocytes. To determine if expression of PHD3 plays a role in endochondral bone formation, we conditionally disrupted the gene in chondrocytes by crossing floxed () mice with mice.
View Article and Find Full Text PDFActa Physiol (Oxf)
January 2021
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
Aim: NG2 cells in the brain are comprised of pericytes and NG2 glia and play an important role in the execution of cerebral hypoxia responses, including the induction of erythropoietin (EPO) in pericytes. Oxygen-dependent angiogenic responses are regulated by hypoxia-inducible factor (HIF), the activity of which is controlled by prolyl 4-hydroxylase domain (PHD) dioxygenases and the von Hippel-Lindau (VHL) tumour suppressor. However, the role of NG2 cells in HIF-regulated cerebral vascular homeostasis is incompletely understood.
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