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

Higinio Dopeso,Angel M Cuesta,Amparo Acker-Palmer,Till Acker,Anne-Theres Henze,Hui-Ke Jiao,Boyan K Garvalov,Liane Jurida,Michael Kracht

doi:10.1158/0008-5472.can-17-1346

Abstract

Lung cancer is the leading cause of cancer-related death worldwide, in large part due to its high propensity to metastasize and to develop therapy resistance. Adaptive responses to hypoxia and epithelial-mesenchymal transition (EMT) are linked to tumor metastasis and drug resistance, but little is known about how oxygen sensing and EMT intersect to control these hallmarks of cancer. Here, we show that the oxygen sensor PHD3 links hypoxic signaling and EMT regulation in the lung tumor microenvironment. PHD3 was repressed by signals that induce EMT and acted as a negative regulator of EMT, metastasis, and therapeutic resistance. PHD3 depletion in tumors, which can be caused by the EMT inducer TGFβ or by promoter methylation, enhanced EMT and spontaneous metastasis via HIF-dependent upregulation of the EGFR ligand TGFα. In turn, TGFα stimulated EGFR, which potentiated SMAD signaling, reinforcing EMT and metastasis. In clinical specimens of lung cancer, reduced PHD3 expression was linked to poor prognosis and to therapeutic resistance against EGFR inhibitors such as erlotinib. Reexpression of PHD3 in lung cancer cells suppressed EMT and metastasis and restored sensitivity to erlotinib. Taken together, our results establish a key function for PHD3 in metastasis and drug resistance and suggest opportunities to improve patient treatment by interfering with the feedforward signaling mechanisms activated by PHD3 silencing.Significance: This study links the oxygen sensor PHD3 to metastasis and drug resistance in cancer, with implications for therapeutic improvement by targeting this system. Cancer Res; 78(7); 1805-19. ©2018 AACR.

Highlights

Metastatic dissemination and the development of therapy resistance are the two leading causes for the limited success of current cancer treatment
There was a profound reduction in the level of PHD3 protein following TGFb treatment, which was mirrored by a downregulation of the PHD3 transcript in the lung carcinoma cell lines A549, H441, and NCH-604A (Fig. 1B and C; Supplementary Fig. S1A and S1B), whereas the expression of PHD1 and PHD2 was more variable or did not change
Our data uncover the molecular mechanism behind the function of PHD3 in epithelial–mesenchymal transition (EMT), showing that hypoxia-inducible factors (HIF) and TGFa mediate the induction of EMT following PHD3 suppression

Summary

Introduction

Metastatic dissemination and the development of therapy resistance are the two leading causes for the limited success of current cancer treatment. Tumor metastasis has been linked to the activation of an epithelial–mesenchymal transition (EMT)-like program, which involves dissociation of cell–cell contacts, enhanced migration and dissemination to distant sites [1]. Multiple aspects of tumor malignancy, including metastasis and drug resistance, are commonly associated with tumor hypoxia, which acts primarily through the prolyl hydroxylase domain (PHD) proteins and the hypoxia-inducible factors Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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