RT Journal Article
T1 Loss of PHD3 allows tumours to overcome hypoxic growth inhibition and sustain proliferation through EGFR
A1 Henze, Anne-Theres
A1 Garvalov, Boyan K.
A1 Seidel, Sascha
A1 Cuesta Martínez, Ángel
A1 Ritter, Mathias
A1 Filatova, Alina
A1 Foss, Franziska
A1 Dopeso, Higinio
A1 Essmann, Clara L.
A1 Maxwell, Patrick H.
A1 Reifenberger, Guido
A1 Carmeliet, Peter
A1 Acker-Palmer, Amparo
A1 Acker, Till
AB 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.
PB Nature Research
SN 2041-1723
YR 2014
FD 2014-11-25
LK https://hdl.handle.net/20.500.14352/93849
UL https://hdl.handle.net/20.500.14352/93849
LA eng
NO Henze AT, Garvalov BK, Seidel S, et al. Loss of PHD3 allows tumours to overcome hypoxic growth inhibition and sustain proliferation through EGFR. Nat Commun. 2014;5:5582. Published 2014 Nov 25. doi:10.1038/ncomms6582
NO Deutsche Krebshilfe
NO German Ministry of Education and Research
NO National Genome Network
NO Brain Tumour Network
NO Behring-Roentgen Foundation
NO KFO210
NO LOEWE-OSF
NO Gutenberg Research College
NO Johannes Gutenberg University Mainz
NO Clusters of Excellence ‘Cardio-Pulmonary System (ECCPS)’
NO Universities of Giessen and Frankfurt
DS Docta Complutense
RD 8 abr 2025