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Epigenetic silencing of prostaglandin E receptor 2 (PTGER2) is associated with progression of neuroblastomas

Oncogene volume 26, pages 7401–7413 (2007)Cite this article

Abstract

We previously identified a cluster of prostanoid receptor genes, prostaglandin D2 receptor (PTGDR) and prostaglandin E receptor 2 (PTGER2), as possible targets for DNA methylation in advanced types of neuroblastoma (NB) using bacterial artificial chromosome array-based methylated CpG island amplification method. Among them, in this study, we found that PTGER2 was frequently silenced in NB cell lines, especially in those with MYCN amplification, through epigenetic mechanisms. In NB cell lines, DNA methylation pattern within a part of CpG island was inversely correlated with PTGER2 expression, and histone H3 and H4 deacetylation and histone H3 lysine 9 methylation within the putative promoter region were more directly correlated with silencing of this gene. Methylation of PTGER2 was observed more frequently in advanced-type of primary NBs compared with early-stage tumors. Growth of NB cells lacking endogenous PTGER2 expression was inhibited by restoration of the gene product by transient and stable transfection. A PTGER2-selective agonist, butaprost, increased intracellular cyclic adenosine monophosphate (cAMP) level, inhibited cell growth and induced apoptosis of NB cells stably expressing exogenous PTGER2. 8-Bromo-cAMP also inhibited growth of NB cells lacking PTGER2 expression, but not cells expressing this gene. Taken together, it is suggested that NB cells may lose responsiveness to PTGER2-mediated growth inhibition/apoptosis through epigenetic silencing of PTGER2 and/or disruption of downstream cAMP-dependent pathway during the neuroblastomagenesis.

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Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research on Priority Areas (C) from the Ministry of Education, Culture, Sports, Science and Technology, Japan; by a Grant-in-Aid from Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Corporation (JST); and by a 21st Century Center of Excellence (COE) Program for Molecular Destruction and Reconstitution of Tooth and Bone.

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Authors and Affiliations

  1. Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan

    Y Sugino, A Misawa, J Inoue, I Imoto & J Inazawa

  2. Core Research for Evolutionary Science and Technology of the Japan Science and Technology Corporation, Saitama, Japan

    Y Sugino, A Misawa, J Inoue, I Imoto & J Inazawa

  3. Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Y Sugino, H Hosoi & T Sugimoto

  4. Department of Pathology and Immunology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

    M Kitagawa

  5. Department of Genome Medicine, Hard Tissue Genome research Center, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

    I Imoto & J Inazawa

  6. 21st Century Center of Excellence Program for Molecular Destruction and Reconstitution of Tooth and Bone, Tokyo Medical and Dental University, Tokyo, Japan

    J Inazawa

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  1. Y Sugino
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Correspondence to J Inazawa.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Sugino, Y., Misawa, A., Inoue, J. et al. Epigenetic silencing of prostaglandin E receptor 2 (PTGER2) is associated with progression of neuroblastomas. Oncogene 26, 7401–7413 (2007). https://doi.org/10.1038/sj.onc.1210550

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