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Nuclear trafficking of EGFR by Vps34 represses Arf expression to promote lung tumor cell survival

Oncogene volume 35, pages 3986–3994 (2016)Cite this article

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Abstract

Epidermal growth factor receptor (EGFR) is a cell surface receptor that has an essential role in cell proliferation and survival, and overexpression of EGFR is a common feature of human cancers. In Non-small-cell lung cancer (NSCLC), activating mutations of EGFR have also been described. We recently showed that mutant EGFR-L858R inhibits the expression of the p14ARF tumor-suppressor protein to promote cell survival. In this study, we defined the molecular bases by which EGFR controls Arf expression. Using various lung tumor models, we showed that EGF stimulation inhibits Arf transcription by a mechanism involving the nuclear transport and recruitment of EGFR to the Arf promoter. We unraveled the vesicular trafficking protein Vps34 as a mediator of EGFR nuclear trafficking and showed that its neutralization prevents the accumulation of EGFR to the Arf promoter in response to ligand activation. Finally, in lung tumor cells that carry mutant EGFR-L858R, we demonstrated that inhibition of Vps34 using small interfering RNA restrains nuclear EGFR location and restores Arf expression leading to apoptosis. These findings identify the Arf tumor suppressor as a new transcriptional target of nuclear EGFR and highlight Vps34 as an important regulator of the nuclear EGFR/Arf survival pathway. As a whole, they provide a mechanistic explanation to the inverse correlation between nuclear expression of EGFR and overall survival in NSCLC patients.

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Acknowledgements

We thank Professor A Gazdar for providing us with the H1719, HCC827 and H1975 cellular models and Dr MC Hung for the CHO-EGFR and CHO-EGFR-pNLS cells. This work was supported by Institut National de la Santé et de la Recherche Médicale U823, the Fondation ARC pour la recherche sur le cancer (grant no. 20131200109), the Fondation de France and the Ligue Nationale contre Le Cancer Comité de Savoie. DD was supported by the Fond de Dotation pour la Recherche en Santé Respiratoire 2010 and the Fondation ARC pour la recherche sur le cancer. MG was supported by le Fonds Agir pour les Maladies Chroniques. A-SH was supported by the French Research Ministry.

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Authors and Affiliations

  1. Equipe Bases Moléculaires de la Progression des Cancers du Poumon, Centre de Recherche INSERM U823, Grenoble, France

    D Dayde, M Guerard, P Perron, A-S Hatat, C Barrial, B Eymin & S Gazzeri

  2. Université Joseph Fourier, Institut Albert Bonniot, Grenoble, France

    D Dayde, M Guerard, P Perron, A-S Hatat, C Barrial, B Eymin & S Gazzeri

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  1. D Dayde
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Correspondence to S Gazzeri.

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Dayde, D., Guerard, M., Perron, P. et al. Nuclear trafficking of EGFR by Vps34 represses Arf expression to promote lung tumor cell survival. Oncogene 35, 3986–3994 (2016). https://doi.org/10.1038/onc.2015.480

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