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Targeted inhibition of genome-wide DNA methylation analysis in epigenetically modulated phenotypes in lung cancer

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Abstract

DNA methylation analysis, an epigenetic specification, has been explored for partial determination of cancer cell phenotypes. The development of metastasis in cancerogenesis has led its feasible association with the epigenetic modulations. We generated highly aggressive non-small cell lung cancer cell lines (HTB56 and A549) by using in vivo selection approach. These were, then, subjected to DNA methylation analysis (genome-wide). We also explored the therapeutic effects of azacytidine, an epigenetic agent, on DNA methylation patterns as well as the in vivo phenotypes. During the development of highly aggressive cell lines, we observed widespread modulations in DNA methylation. Reduced representation bisulfite sequencing was used and compared with the less aggressive parental cell lines to identify the differential methylation, which was achieved up to 2.7 % of CpG-rich region. Azacytidine inhibited DNA methyltransferase and reversed the prometastatic phenotype. We found its high association with the preferential loss of DNA methylation from hypermethylated sites. After persisted exposure of azacytidine, we observed that DNA methylation affected the polycomb-binding sites. We found close association of DNA methylome modifications with metastatic capability of non-small cell lung cancer. We also concluded that epigenetic modulation could be used as a potential therapeutic approach to prevent metastasis formation as prometastatic phenotype was reversed due to inhibition of DNA methyltransferase.

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    Authors and Affiliations

    1. Department of Medical Imaging, Linyi People’s Hospital, Linyi, Shandong, China

      Shou-Ping Dai

    2. The Third Department of Internal Medicine, Shandong Cancer Hospital, Jinan, Shandong, China

      Chao Xie

    3. Department of Radiology, The Maternal and Child Health Hospital of Zaozhuang, Zaozhuang, Shandong, China

      Ning Ding

    4. Department of Geriatrics, The Second People’s Hospital of Yanzhou Mining Bureau, Zoucheng, China

      Yi-Jun Zhang

    5. Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China

      Lei Han

    6. Department of Oncology, Affiliated Hospital of Luzhou Medical College, No. 25 Taiping Street, Luzhou, Sichuan, 646000, China

      Yun-Wei Han

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    1. Shou-Ping Dai
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    2. Chao Xie
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    4. Yi-Jun Zhang
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    Correspondence to Yun-Wei Han.

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    Shou-Ping Dai and Chao Xie have contributed equally to this work.

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    Dai, SP., Xie, C., Ding, N. et al. Targeted inhibition of genome-wide DNA methylation analysis in epigenetically modulated phenotypes in lung cancer. Med Oncol 32, 176 (2015). https://doi.org/10.1007/s12032-015-0615-x

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    • DOI: https://doi.org/10.1007/s12032-015-0615-x

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