title: Regulation of protein kinase C-related kinase (PRK) signalling by the TPα and TPβ isoforms of the human thromboxane A2receptor: Implications for thromboxane- and androgen- dependent neoplastic and epigenetic responses in prostate cancer.
abstract: The prostanoid thromboxane (TX) A2and its T Prostanoid receptor (the TP) are increasingly implicated in prostate cancer (PCa). Mechanistically, we recently discovered that both TPα and TPβ form functional signalling complexes with members of the protein kinase C-related kinase (PRK) family, AGC- kinases essential for the epigenetic regulation of androgen receptor (AR)-dependent transcription and promising therapeutic targets for treatment of castrate-resistant prostate cancer (CRPC). Critically, similar to androgens, activation of the PRKs through the TXA2/TP signalling axis induces phosphorylation of histone H3 at Thr11 (H3Thr11), a marker of androgen-induced chromatin remodelling and transcriptional activation, raising the possibility that TXA2-TP signalling can mimic and/or enhance AR-induced cellular changes even in the absence of circulating androgens such as in CRPC. Hence the aim of the current study was to investigate whether TXA2/TP-induced PRK activation can mimic and/or enhance AR-mediated cellular responses in the model androgen-responsive prostate adenocarcinoma LNCaP cell line. We reveal that TXA2/TP signalling can act as a neoplastic- and epigenetic-regulator, promoting and enhancing both AR-associated chromatin remodelling (H3Thr11 phosphorylation, WDR5 recruitment and acetylation of histone H4 at lysine 16) and AR-mediated transcriptional activation (e.g of the KLK3/prostate-specific antigen and TMPRSS2 genes) through mechanisms involving TPα/TPβ mediated-PRK1 and PRK2, but not PRK3, signalling complexes. Overall, these data demonstrate that TPα/TPβ can act as neoplastic and epigenetic regulators by mimicking and/or enhancing the actions of androgens within the prostate and provides further mechanistic insights into the role of the TXA2/TP signalling axis in PCa, including potentially in CRPC.
authors.affiliation: UCD School of Biomolecular and Biomedical Sciences, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Aine G
authors.initials: AG
authors.lastname: O'Sullivan
authors.affiliation: UCD School of Biomolecular and Biomedical Sciences, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Eamon P
authors.initials: EP
authors.lastname: Mulvaney
authors.affiliation: UCD School of Biomolecular and Biomedical Sciences, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. Electronic address: therese.kinsella@ucd.ie.
authors.forename: B Therese
authors.initials: BT
authors.lastname: Kinsella
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000728:Androgens / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013928:Thromboxane A2 / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000728:Androgens; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2; D017346:Protein Serine-Threonine Kinases
keywords: Androgen; Epigenetics; Prostate cancer; Protein kinase C-related kinase; Receptor; Thromboxane