Abstract
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.
Highlights
Solid tumours are exposed to microenvironmental factors such as hypoxia that normally inhibit cell growth
These results suggested that PHD3 expression levels are attenuated in glioma progression and, importantly, are kept low even though tumours activate the hypoxic response
PHD3 genetic loss was associated with downregulation of PHD3 expression (Supplementary Fig. 1d), suggesting that single-copy loss of PHD3 may contribute in part to clonal selection of cells carrying this broad deletion
Summary
Solid tumours are exposed to microenvironmental factors such as hypoxia that normally inhibit cell growth. We corroborated our results in the primary glioblastoma cell line GBM046x, isolated from a patient biopsy, in which PHD3 silencing significantly promoted intracranial tumour growth (Supplementary Fig. 3a–c). To functionally corroborate this role of PHD3 in tumour growth suppression we used G55 cells with increased PHD3 expression levels, and control G55 cells expressing green fluorescent protein (GFP).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
