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

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.

• Authors: Y Sugino, A Misawa, J Inoue, M Kitagawa, H Hosoi, T Sugimoto, I Imoto, J Inazawa
• Journal: Oncogene (Oncogene) Vol. 26 Issue 53 Pg. 7401-13 (Nov 22 2007) ISSN: 1476-5594 [Electronic] England
• PMID: 17533365 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• PTGER2 protein, human
• RNA, Messenger
• Receptors, Immunologic
• Receptors, Prostaglandin
• Receptors, Prostaglandin E
• Receptors, Prostaglandin E, EP2 Subtype
• 8-Bromo Cyclic Adenosine Monophosphate
• Alprostadil
• butaprost
• Dinoprostone
• prostaglandin D2 receptor

Topics

• 8-Bromo Cyclic Adenosine Monophosphate (pharmacology)
• Alprostadil (analogs & derivatives, pharmacology)
• Cell Growth Processes (drug effects, genetics)
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• CpG Islands
• DNA Methylation
• Dinoprostone (pharmacology)
• Disease Progression
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Genes, Tumor Suppressor
• Humans
• Neuroblastoma (genetics, metabolism, pathology)
• Promoter Regions, Genetic
• RNA, Messenger (biosynthesis, genetics)
• Receptors, Immunologic (biosynthesis, genetics)
• Receptors, Prostaglandin (biosynthesis, genetics)
• Receptors, Prostaglandin E (biosynthesis, genetics)
• Receptors, Prostaglandin E, EP2 Subtype