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Chidamide alleviates TGF-β-induced epithelial–mesenchymal transition in lung cancer cell lines

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Abstract

Transforming growth factor-β (TGF-β)-induced epithelial–mesenchymal transition is a critical process in the initiation of metastasis of various types of cancer. Chidamide is a class I histone deacetylase inhibitor with anti-tumor activity. This study investigated the effects of chidamide on TGF-β-mediated suppression of E-cadherin expression in adenocarcinomic lung epithelial cells and the molecular mechanisms involved in these effects. Western blot analysis, confocal microscopy, Quantitative methyl-specific PCR and bisulfite sequencing were used to evaluate the effects of different treatments on chidamide ameliorating TGF-β induced-E-cadherin loss. H3 acetylation binding to the promoter of E-cadherin was detected by chromatin immunoprecipitations (CHIP). We found that chidamide reduced the level of lung cancer cell migration observed using a Boyden chamber assay (as an indicator of metastatic potential). Chidamide inhibited TGF-β-induced SMAD2 phosphorylation and attenuated TGF-β-induced loss of E-cadherin expression in lung cancer cells by Western blotting and confocal microscopy, respectively. Quantitative methyl-specific PCR and bisulfite sequencing revealed that TGF-β-enhanced E-cadherin promoter methylation was ameliorated in cells treated with chidamide. We demonstrated that histone H3 deacetylation within the E-cadherin promoter was required for TGF-β-induced E-cadherin loss; cell treatment with chidamide increased the H3 acetylation detected by CHIP. Taken together, our results demonstrate that TGF-β suppressed E-cadherin expression by regulating promoter methylation and histone H3 acetylation. Chidamide significantly enhanced E-cadherin expression in TGF-β-treated cells and inhibited lung cancer cell migration. These findings indicate that chidamide has a potential therapeutic use due to its capacity to prevent cancer cell metastasis.

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Acknowledgments

This study was supported by Grants from Changhua Christian Hospital of Taiwan (Grant Nos. 101-CCH-IRP-49 and 102-CCH-IRP-004) and the Ministry of Science and Technology of Taiwan (Grant No. 103-2314-B-371-001-MY2). Contract Grant sponsor: Changhua Christian Hospital of Taiwan and Ministry of Science and Technology of Taiwan. Contract Grant Numbers: 101-CCH-IRP-49, 102-CCH-IRP-004, and 103-2314-B-371-001-MY2.

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    Authors and Affiliations

    1. Institute of Biomedical Science, College of Life Sciences, National Chung Hsing University, 250, Guoguang Road, Taichung, 40227, Taiwan

      Sheng-Hao Lin, Ching-Hsiung Lin & Jeremy J. W. Chen

    2. Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan

      Sheng-Hao Lin & Ching-Hsiung Lin

    3. Division of Thoracic Surgery, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan

      Bing-Yen Wang

    4. School of Medicine, National Yang-Ming University, Taipei, Taiwan

      Bing-Yen Wang

    5. Department of Respiratory Care, College of Health Sciences, Chang Jung Christian University, Tainan, Taiwan

      Ching-Hsiung Lin

    6. Institute of Medicine, Chung Shan Medical University, 110, Sec. 1, Chien-Kuo N. Road, Taichung, 40203, Taiwan

      Peng-Ju Chien, Yueh-Feng Wu & Jiunn-Liang Ko

    7. Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan

      Jiunn-Liang Ko

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    1. Sheng-Hao Lin
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    Correspondence to Jiunn-Liang Ko or Jeremy J. W. Chen.

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    Sheng-Hao Lin and Bing-Yen Wang have equally contributed to this study.

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    Lin, SH., Wang, BY., Lin, CH. et al. Chidamide alleviates TGF-β-induced epithelial–mesenchymal transition in lung cancer cell lines. Mol Biol Rep 43, 687–695 (2016). https://doi.org/10.1007/s11033-016-4005-z

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    • DOI: https://doi.org/10.1007/s11033-016-4005-z

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