VEGF/VEGFR-2 upregulates EZH2 expression in lung adenocarcinoma cells and EZH2 depletion enhances the response to platinum-based and VEGFR-2-targeted therapy

Erick Riquelme, Milind Suraokar, Carmen Behrens, Heather Y. Lin, Luc Girard, Monique B. Nilsson, George Simon, Jing Wang, Kevin R. Coombes, J. Jack Lee, Waun Ki Hong, John Heymach, John D. Minna, Ignacio I. Wistuba

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Purpose: To investigate the mechanisms of regulation and role associated with enhancer of zeste homolog 2 (EZH2) expression in lung cancer cells. Experimental Design: We investigated the mechanisms of EZH2 expression associated with the VEGF/VEGFR-2 pathway. Furthermore, we sought to determine the role of EZH2 in response of lung adenocarcinoma to platinum-based chemotherapy, as well as the effect of EZH2 depletion on VEGFR-2-targeted therapy in lung adenocarcinoma cell lines. In addition, we characterized EZH2 expression in lung adenocarcinoma specimens and correlated it with patients' clinical characteristics. Results: In this study, we demonstrate that VEGF/VEGFR-2 activation induces expression of EZH2 through the upregulation of E2F3 and hypoxia-inducible factor-1α (HIF1α), and downregulated expression of miR-101. EZH2 depletion by treatment with 3-deazaneplanocin A and knockdown by siRNA decreased the expression of EZH2 and H3K27me3, increased PARP-C level, reduced cell proliferation and migration, and increased sensitivity of the cells to treatment with cisplatin and carboplatin. In addition, high EZH2 expression was associated with poor overall survival in patients who received platinum-based adjuvant therapy, but not in patients whodid not receive this therapy. Furthermore, we demonstrated for the first time that the inhibition of EZH2 greatly increased the sensitivity of lung adenocarcinoma cells to the anti-VEGFR-2 drug AZD2171. Conclusion: Our results suggest that the VEGF/VEGFR-2 pathway plays a role in regulation of EZH2 expression via E2F3, HIF1α, and miR-101. EZH2 depletion decreases the malignant potential of lung adenocarcinoma and sensitivity of the cells to both platinum-based and VEGFR-2-targeted therapy.

Original languageEnglish (US)
Pages (from-to)3849-3861
Number of pages13
JournalClinical Cancer Research
Volume20
Issue number14
DOIs
Publication statusPublished - Jul 15 2014

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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