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The Role of Histone Deacetylase in the Maintenance of Gefitinib-Resistant Lung Cancer Stem Cells with Epidermal Growth Factor Receptor Mutation
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A2697 - The Role of Histone Deacetylase in the Maintenance of Gefitinib-Resistant Lung Cancer Stem Cells with Epidermal Growth Factor Receptor Mutation
Author Block: F. Nurwidya1, F. Takahashi2, M. Hidayat2, A. Wirawan2, H. Baskoro2, M. Kato3, K. Tajima4, N. Shimada2, S. L. Andarini1, F. Yunus1, K. Takahashi5; 1Department of Pulmonology and Respiratory Medicine, Universitas Indonesia Faculty of Medicine, Jakarta, Indonesia, 2Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan, 3Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan, 4Department of Respiratory Medicine, Juntendo University, Tokyo, Japan, 5Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
Rationale: Histone deacetylase (HDAC) are important in the epigenetic alteration of cancer stem cells (CSCs) that result in chromatin condensation. Our previous study has revealed the existence of gefitinib-resistant-persisters (GRP) population within the non-small cell lung cancer (NSCLC) cells that possesses CSCs features. In the current study, we aimed to clarify the role of HDAC in the gefitinib-resistant lung CSC. Methods: 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 mice after two weeks of gefitinib treatment. Results: 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: Taken together, HDAC is implicated in the CSC phenotype and is involved in the resistance to EGFR-TKI in NSCLC.
Author Block: F. Nurwidya1, F. Takahashi2, M. Hidayat2, A. Wirawan2, H. Baskoro2, M. Kato3, K. Tajima4, N. Shimada2, S. L. Andarini1, F. Yunus1, K. Takahashi5; 1Department of Pulmonology and Respiratory Medicine, Universitas Indonesia Faculty of Medicine, Jakarta, Indonesia, 2Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan, 3Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan, 4Department of Respiratory Medicine, Juntendo University, Tokyo, Japan, 5Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
Rationale: Histone deacetylase (HDAC) are important in the epigenetic alteration of cancer stem cells (CSCs) that result in chromatin condensation. Our previous study has revealed the existence of gefitinib-resistant-persisters (GRP) population within the non-small cell lung cancer (NSCLC) cells that possesses CSCs features. In the current study, we aimed to clarify the role of HDAC in the gefitinib-resistant lung CSC. Methods: 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 mice after two weeks of gefitinib treatment. Results: 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: Taken together, HDAC is implicated in the CSC phenotype and is involved in the resistance to EGFR-TKI in NSCLC.
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