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

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-1? (HIF1?), 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 who did 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, HIF1?, 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.

SUBMITTER: Riquelme E

PROVIDER: S-EPMC4190586 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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

Riquelme Erick E Suraokar Milind M Behrens Carmen C Lin Heather Y HY Girard Luc L Nilsson Monique B MB Simon George G Wang Jing J Coombes Kevin R KR Lee J Jack JJ Hong Waun Ki WK Heymach John J Minna John D JD Wistuba Ignacio I II

Clinical cancer research : an official journal of the American Association for Cancer Research 20140521 14

<h4>Purpose</h4>To investigate the mechanisms of regulation and role associated with enhancer of zeste homolog 2 (EZH2) expression in lung cancer cells.<h4>Experimental design</h4>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 ad ...[more]

PMID: 24850841

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Project description:BACKGROUND:Glioblastoma (GBM) is the most common primary tumor in the brain, and the median survival time for GBM patients is only about 14 months; therefore, there is an urgent need for new and more effective strategies. Since cell cycle disorder is a key factor in tumor progression and immortalization, there is great potential for controlling cell cycle disorders in tumor cells in GBM patients. We began to study a novel combination of AQB and palbociclib to evaluate its potential as a new therapeutic target. METHODS:Protein mass spectrometry was used to identify the tumor suppressor genes up-regulated by AQB.The effects of HOTAIR - EZH2 inhibitor AQB and CDK4/6 inhibitor Palbociclib on glioma cells lines were examined in vitro and in vivo experiments. RESULTS:The combination of AQB and palbociclib inhibitors has a more pronounced suppression effect on the cell cycle, especially gliomas with high expression of HOTAIR and EZH2 and low expression of CWF19L1. We performed protein mass spectrometry to identify AQB upregulated tumor suppressor genes and confirmed that CWF19L1 is regulated by H3K27ac through chromatin immunoprecipitation-quantitative PCR results. Univariate and multivariate Cox regression analysis and database analysis were performed to suggest CWF19L1 is a good prognostic factor. Our experimental results suggested that CWF19L1 can be significantly upregulated by AQB and lead to degradation of CDK4/6, resulting in G1 arrest. The combination of AQB and CDK4/6 inhibitor palbociclib is more effective in inhibiting the growth of glioma than in the single drug, both in vivo and in vitro. Similarly, we found that both AQB and palbociclib can inhibit Wnt/?-catenin signaling, and the combined use of the two inhibitors has a stronger inhibitory effect on tumor metastasis. CONCLUSIONS:The combination of AQB and CDK4/6 inhibitor palbociclib has been found to have significant antitumor effects, which is likely to become a new strategy for glioma treatment.

Dataset Information

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

Publications

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

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