Abstract
Androgen dependent induction of the ETS related gene (ERG) expression in more than half of all prostate cancers results from gene fusions involving regulatory sequence of androgen regulated genes (i.e. TMPRSS2, SLC45A3 and NDRG1) and protein coding sequence of the ERG. Emerging studies in experimental models underscore the functions of ERG in prostate tumorigenesis. However, biological and biochemical functions of ERG in prostate cancer (CaP) remain to be elucidated. This study suggests that ERG activation plays a role in prostaglandin signaling because knockdown of ERG expression in TMPRSS2-ERG fusion containing CaP cells leads to altered levels of the 15-hydroxy-prostaglandin dehydrogenase (HPGD), a tumor suppressor and prostaglandin catabolizing enzyme, and prostaglandin E2 (PGE2) . We demonstrate that HPGD expression is regulated by the binding of the ERG protein to the core promoter of this gene. Moreover, prostaglandin E2 dependent cell growth and urokinase-type plasminogen activator (uPA) expression are also affected by ERG knockdown. Together, these data imply that the ERG oncoprotein in CaP cells positively influence prostaglandin mediated signaling, which may contribute to tumor progression.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dinoprostone / metabolism*
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Dinoprostone / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics
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Gene Knockdown Techniques
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Humans
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Hydroxyprostaglandin Dehydrogenases / genetics
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Hydroxyprostaglandin Dehydrogenases / metabolism
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Interleukin-1beta / pharmacology
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Male
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Models, Biological
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Promoter Regions, Genetic
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Prostatic Neoplasms / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / pharmacology
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Receptors, Prostaglandin E, EP4 Subtype / metabolism
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Signal Transduction* / drug effects
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Trans-Activators / pharmacology
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Transcriptional Regulator ERG
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Urokinase-Type Plasminogen Activator / metabolism
Substances
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ERG protein, human
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Interleukin-1beta
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Oncogene Proteins, Fusion
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RNA, Small Interfering
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Receptors, Prostaglandin E, EP4 Subtype
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TMPRSS2-ERG fusion protein, human
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Trans-Activators
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Transcriptional Regulator ERG
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Hydroxyprostaglandin Dehydrogenases
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15-hydroxyprostaglandin dehydrogenase
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Urokinase-Type Plasminogen Activator
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Dinoprostone