Loss of PHD3 allows tumours to overcome hypoxic growth inhibition and sustain proliferation through EGFR

• DOI: 10.1038/ncomms6582
• Publication Date: 2014-11-25T11:44:27Z
• Authors: Anne-Theres Henze; Boyan K. Garvalov; Sascha Seidel; Angel M. Cuesta; Mathias Ritter; Alina Filatova; Franziska Foss; Higinio Dopeso; Clara L. Essmann; Patrick H. Maxwell; Guido Reifenberger; Peter Carmeliet; Amparo Acker-Palmer; Till Acker
• Keywords: Male; Mice, Knockout; 0301 basic medicine; 0303 health sciences; 24 Ciencias de la Vida; Procollagen-Proline Dioxygenase; Apoptosis; Hypoxia-Inducible Factor 1, alpha Subunit; Article; Hypoxia-Inducible Factor-Proline Dioxygenases; 3. Good health; 12. Responsible consumption; ErbB Receptors; Oxygen; Gene Knockout Techniques; 03 medical and health sciences; Ciencias Biomédicas; Cell Line, Tumor; Animals; Humans; Female; Glioblastoma; Hypoxia; Cell Proliferation

AbstractSolid 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.