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I. Kobayashi



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    P1.02 - Biology/Pathology (ID 614)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-065 - Histone Deacetylase Inhibition Alters Stem Cell Phenotype in Gefitinib-Resistant Lung Cancer Cells with EGFR Mutation (ID 7401)

      09:30 - 16:00  |  Author(s): I. Kobayashi

      • Abstract

      Background:
      Cancer stem cells (CSCs) are epigenetically altered by histone deacetylase (HDAC), resulting in chromatin condensation. We have reported that gefitinib-resistant-persisters (GRP) population within non-small cell lung cancer (NSCLC) cells possesses CSCs features. The purpose of this study is to examine the role of HDAC in the gefitinib-resistant lung CSC.

      Method:
      We used HDAC1, HDAC2, and HDAC5 as markers of chromatin compaction in GRP of EGFR-mutant NSCLC cells PC9 and HCC827. Gefitinib-resistant tumor (GRT) was established by obtaining the remaining tumor in PC9-injected NOG mice after two weeks of gefitinib treatment. Quantitative real-time PCR were performed to analyze gene expressions. immunofluorescence and fluorescence-immunohistochemistry were performed to analyze protein expressions in the NSCLC cell lines and in vivo biopsy specimens, respectively. HDAC inhibitor Trichostatin-A was used to study the impact on the sensitivity of GRP to gefitinib and the implication on the CSC features.

      Result:
      PC9-GRP and HCC827-GRP cells expressed high level of HDAC1, HDAC2, and HDAC5. GRT also showed upregulation of HDAC1 compared to naïve PC9 tumor. Inhibition of HDAC reduced CSC-related factors and, reduced sphere formation of GRP, and increased sensitivity to gefitinib. Specimens from lung cancer patients with acquired resistance to gefitinib displayed high expression of HDAC1.

      Conclusion:
      HDAC is implicated in the CSC phenotype and is involved in the resistance to EGFR-TKI in NSCLC. Inhition of HDAC could be considered to reverse acquired resistance of EGFR-mutant to EGFR-TKI that is mediated by CSC.

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    P2.02 - Biology/Pathology (ID 616)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.02-012 - The Epigenetic Role of LSD1+8a in Small Cell Lung Cancer (ID 8848)

      09:30 - 16:00  |  Author(s): I. Kobayashi

      • Abstract

      Background:
      Small cell lung cancer (SCLC) is a neuroendocrine tumor which account for 15% of all lung cancers. SCLC is characterized by rapid progression which led metastasis to distant organs and represented poor prognosis. Although there were various molecular targeted therapies in SCLC that were already under investigation, results have been disappointing. The focus on biological pathways has recently shifted from genetic to epigenetic regulations. Histone methylation is one of the epigenetic mechanism which has pivotal role in gene expression, cell cycle and differentiation. Lysine-specific demethylase 1 (LSD1)/KDM1 is a histone modifier that is expressed in certain human cancers including SCLC. LSD1+8a is one of the isoform of LSD1 that was reported to be restricted in neural tissues and it plays critical role in neuronal differentiation. The aim of this study is to elucidate the epigenetic role of LSD1+8a in SCLC.

      Method:
      The expression of LSD1 and LSD1+8a mRNAs were analyzed by qPCR in several cancer cell lines. Neuroendocrine markers were detected by qPCR in several SCLC cell lines. The Pearson correlation test was performed to investigate the correlation between LSD1+8a and neuroendocrine markers. siRNA against specific to exon 8a was designed and knockdown LSD1+8a isoform specifically. Cell proliferation assays following knockdown of LSD1+8a were performed in LSD1+8a expressed SCLC cell lines.

      Result:
      LSD1 mRNA was expressed in majority of SCLC cell lines, interestingly LSD1+8a mRNA was detected in small subset of SCLC cell lines. There were positive correlations of LSD1+8a and neuroendocrine marker genes such as chromogranin A (CHGA), enolase2 (ENO2), neural cell adhesion molecule (NCAM) and synaptophysin (SYP) in human cancer cell lines. The suppression of LSD1+8a by siRNA drove to decrease expression of neuroendocrine marker genes in SCLC and inhibited cell proliferation in LSD1+8a expressed cell.

      Conclusion:
      LSD1+8a could play an important role in SCLC.