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Aberrant GATA2 epigenetic dysregulation induces a GATA2/GATA6 switch in human gastric cancer

Oncogene volume 37, pages 993–1004 (2018)Cite this article

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Abstract

Six GATA transcription factors play important roles in eukaryotic development. Among these, GATA2, an essential factor for the hematopoietic cell lineage, exhibits low expression in human gastric tissues, whereas GATA6, which is crucial for gastrointestinal development and differentiation, is frequently amplified and/or overexpressed in human gastric cancer. Interestingly, we found that GATA6 was overexpressed in human gastric cancer cells only when GATA2 expression was completely absent, thereby showing an inverse correlation between GATA2 and GATA6. In gastric cancer cells that express high GATA6 levels, a GATA2 CpG island is hypermethylated, repressing expression in these cells. In contrast, GATA6 expression is undetectable in GATA2-overexpressing gastric cancer cells, which lack GATA2 DNA methylation. Furthermore, PRC2 complex-mediated transcriptional silencing of GATA6 was observed in the GATA2-overexpressing cells. We also show that the GATA2 and PRC2 complexes are enriched within the GATA6 locus, and that the recruitment of the PRC2 complex is impaired by disrupting GATA2 expression, resulting in GATA6 upregulation. In addition, ectopic GATA2 expression significantly downregulates GATA6 expression, suggesting GATA2 directly represses GATA6. Furthermore, GATA6 downregulation showed antitumor activity by inducing growth arrest. Finally, we show that aberrant GATA2 methylation occurs early during the multistep process of gastric carcinogenesis regardless of Helicobacter pylori infection. Taken together, GATA2 dysregulation by epigenetic modification is associated with unfavorable phenotypes in human gastric cancer cells by allowing GATA6 expression.

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Acknowledgements

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (HI14C1277), by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning, Republic of Korea (NRF-2016M3A9B6026918, NRF-2016M3A9B6026921 and 2011-0030049) and by Basic Science Research Program through the NRF funded by the Ministry of Education, Republic of Korea (NRF-2016R1D1A1B03930736).

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  1. S H Song and M S Jeon: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Genomics Research Laboratory, Cancer Research Institute, Seoul National University, Seoul, Republic of Korea

    S H Song, M S Jeon, J W Nam, J K Kang, Y J Lee, J Y Kang, H P Kim, S W Han & T Y Kim

  2. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea

    M S Jeon, J W Nam, J K Kang, Y J Lee, J Y Kang, H P Kim & T Y Kim

  3. Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea

    S W Han & T Y Kim

  4. Laboratory of Epigenetics, Cancer Research Institute, Seoul National University, Seoul, Republic of Korea

    G H Kang

  5. Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea

    G H Kang

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Song, S., Jeon, M., Nam, J. et al. Aberrant GATA2 epigenetic dysregulation induces a GATA2/GATA6 switch in human gastric cancer. Oncogene 37, 993–1004 (2018). https://doi.org/10.1038/onc.2017.397

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