PHD3 regulates EGFR internalization and signalling in tumours

Abstract

Tumours exploit their hypoxic microenvironment to induce a more aggressive phenotype, while curtailing the growth-inhibitory effects of hypoxia through mechanisms that are poorly understood. The prolyl hydroxylase PHD3 is regulated by hypoxia and plays an important role in tumour progression. Here we identify PHD3 as a central regulator of epidermal growth factor receptor (EGFR) activity through the control of EGFR internalization to restrain tumour growth. PHD3 controls EGFR activity by acting as a scaffolding protein that associates with the endocytic adaptor Eps15 and promotes the internalization of EGFR. In consequence, loss of PHD3 in tumour cells suppresses EGFR internalization and hyperactivates EGFR signalling to enhance cell proliferation and survival. Our findings reveal that PHD3 inactivation provides a novel route of EGFR activation to sustain proliferative signalling in the hypoxic microenvironment.

Association of PHD3 and HIF2α gene expression with clinicopathological characteristics in human hepatocellular carcinoma

“…The present study aimed to explore the association between PHD3 and HIF2α expression in HCC (under hypoxic conditions). Several studies have demonstrated that PHD3 serves a novel role in the progression and prognosis of cancer (15-24); PHD3 is also able to induce apoptosis and inhibit proliferation in cancer cells (22)(23)(24)(25)(26)(27)(28)(29). To the best of our knowledge, the present study is the first to report that PHD3 overexpression induces apoptosis and inhibits growth and proliferation in HCC cells.…”

“…Given the increasing number of observational studies on PHD3, considerable attention has been focused on the mechanism of PHD3 (17,18,(24)(25)(26)(27)(28). Su et al (18) revealed that PHD3-induced apoptosis is dependent on nerve growth factor by activating caspase-3 in pancreatic cancer.…”

“…PHD3 is also able to be regulated by the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway in renal cell carcinoma (17). Recent studies have demonstrated that PHD3 suppresses tumor growth by regulating the epidermal growth factor receptor activity (26,27). In our previous study, a vector containing the PHD3 gene was transfected into HepG2 cells and PHD3 overexpression was revealed to inhibit cell proliferation and induce apoptosis by activating caspase-3 (28).…”

PHD3 Controls Lung Cancer Metastasis and Resistance to EGFR Inhibitors through TGFα

“…These findings are in line with previous studies showing that lung carcinomas often co-overexpress EGFR together with TGFα in an autocrine loop to sustain EGFR hyperactivation (46). Interestingly, we have previously shown that PHD3 is a central regulator of EGFR activity through the control of EGFR internalization in glioma (10,11). This endocytic adaptor function of PHD3 in gliomas is independent of the PHD3 hydroxylase activity and HIFs, indicating that PHD3 may impact on the EGFR pathway at different levels and in a tumor entity specific manner.…”

“…The role of PHDs in tumor growth is incompletely understood. While some studies have demonstrated that PHD deficiency can reduce tumor growth, metastasis or therapy resistance (3)(4)(5)(6), other reports highlight a role of PHDs as tumor suppressors (7)(8)(9)(10)(11)(12)(13).…”