title: Retinoic acid and androgen receptors combine to achieve tissue specific control of human prostatic transglutaminase expression: a novel regulatory network with broader significance.
abstract: In the human prostate, expression of prostate-specific genes is known to be directly regulated by the androgen-induced stimulation of the androgen receptor (AR). However, less is known about the expression control of the prostate-restricted TGM4 (hTGP) gene. In the present study we demonstrate that the regulation of the hTGP gene depends mainly on retinoic acid (RA). We provide evidence that the retinoic acid receptor gamma (RAR-G) plays a major role in the regulation of the hTGP gene and that presence of the AR, but not its transcriptional transactivation activity, is critical for hTGP transcription. RA and androgen responsive elements (RARE and ARE) were mapped to the hTGP promoter by chromatin immunoprecipitation (ChIP), which also indicated that the active ARE and RARE sites were adjacent, suggesting that the antagonistic effect of androgen and RA is related to the relative position of binding sites. Publicly available AR and RAR ChIP-seq data was used to find gene potentially regulated by AR and RAR. Four of these genes (CDCA7L, CDK6, BTG1 and SAMD3) were tested for RAR and AR binding and two of them (CDCA7L and CDK6) proved to be antagonistically regulated by androgens and RA confirming that this regulation is not particular of hTGP.
authors.affiliation: Department of Biology, Yorkshire Cancer Research Unit, University of York, Heslington, York YO10 5DD, UK.
authors.forename: Guillermo C
authors.initials: GC
authors.lastname: Rivera-Gonzalez
authors.forename: Alastair P
authors.initials: AP
authors.lastname: Droop
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Rippon
authors.forename: Katrin
authors.initials: K
authors.lastname: Tiemann
authors.forename: Davide
authors.initials: D
authors.lastname: Pellacani
authors.forename: Lindsay J
authors.initials: LJ
authors.lastname: Georgopoulos
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Maitland
mesh_terms: D000728:Androgens / Q000494:pharmacology; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000201:enzymology* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics; D011944:Receptors, Androgen / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism* / Q000502:physiology; D015533:Transcriptional Activation; D011503:Transglutaminases / Q000235:genetics* / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D000097768:Retinoic Acid Receptor gamma
chemical_list: D000728:Androgens; D015741:Metribolone; D011944:Receptors, Androgen; D018168:Receptors, Retinoic Acid; D011503:Transglutaminases; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C418702:transglutaminase 4