Regulation of protein kinase C-related kinase (PRK) signalling by the TPα and TPβ isoforms of the human thromboxane A2 receptor: Implications for thromboxane- and androgen- dependent neoplastic and epigenetic responses in prostate cancer

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1863

Article

O'Sullivan, Aine G.¹  Mulvaney, Eamon P.¹  Kinsella, B. Therese¹ 

[1] Univ Coll Dublin, UCD Conway Inst Biomol & Biomed Res, UCD Sch Biomol & Biomed Sci, Dublin 4, Ireland

关键词: Thromboxane;    Receptor;    Androgen;    Prostate cancer;    Protein kinase C-related kinase;    Epigenetics;   

DOI  :  10.1016/j.bbadis.2017.01.011

来源: Elsevier

【 摘 要 】

The prostanoid thromboxane (TX) A(2) and its T Prostanoid receptor (the TP) are increasingly implicated in prostate cancer (PCa). Mechanistically, we recently discovered that both TP alpha and TP beta 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 TXA(2)/TP signalling axis induces phosphorylation of histone H3 at Thrli (H3Thr11), a marker of androgen-induced chromatin remodelling and transcriptional activation, raising the possibility that TXA(2)-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 TXA(2)/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 TXA(2)/TP signalling can act as a neoplastic- and epigenetic-regulator, promoting and enhancing both AR-associated chromatin remodelling (H3Thrl 1 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 TP alpha/TP beta mediated-PRK1 and PRK2, but not PRK3, signalling complexes. Overall, these data demonstrate that TP alpha/TP beta 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 TXA(2)/TP signalling axis in PCa, including potentially in CRPC. (C) 2017 Elsevier B.V. All rights reserved.

【 授权许可】

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