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J. Kikuchi

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    P1.01 - Poster Session 1 - Cancer Biology (ID 143)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.01-014 - Effects of combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor and the histone deacetylase inhibitor on NSCLC cells. (ID 2680)

      09:30 - 16:30  |  Author(s): J. Kikuchi

      • Abstract

      EZH2, a polycomb group protein, has histone methyltransferase activity, and is involved in malignant transformation of several cancers. We have previously shown that an EZH2 inhibitor, DZNep, inhibits growth of non-small cell lung cancer (NSCLC) cell lines via G1 arrest and apoptosis. Recent studies have shown that EZH2-mediated gene silencing requires a recruitment of the histone deacetylase (HDAC) activity. Co-treatment with DZNep and an HDAC inhibitor has been shown to induce apoptosis synergistically in AML, ovarian cancers and renal cancers. However, the effect of combined therapy with DZNep and an HDAC inhibitor on NSCLC cells has not been reported.

      We evaluated the effect of combined therapy with DZNep and an HDAC inhibitor, SAHA, on four human NSCLC cell lines, H1299, H1975, A549 and PC-3. Cell proliferation of untreated or drug-treated cells was measured by MTT assay. Percentage of apoptotic cells was measured using FITC-conjugated annexin V with a flow cytometer. Western blot analysis was performed on total cell lysates.

      Co-treatment with DZNep and SAHA inhibited cell proliferation synergistically, and reduced EZH2 expression and histone H3 lysine 27 trimethylation more effectively compared with each agent alone. The co-treatment greatly induced accumulation of p27[ Kip1] and decrease in cyclin A expression. Flow cytometry analysis demonstrated that the apoptotic fraction was increased in an additive or synergistic manner by the combination therapy. These effects were more evident in H1975 and PC-3 cells with EGFR mutation, in which expression of EGFR and phosphorylation of EGFR, AKT and ERK1/2 were markedly decreased by the co-treatment.

      Combined epigenetic therapy with an EZH2 inhibitor and an HDAC inhibitor may represent an effective strategy for NSCLCs.