Par14 interacts with the androgen receptor, augmenting both its transcriptional activity and prostate cancer proliferation.
Par14 interacts with the androgen receptor, augmenting both its transcriptional activity and prostate cancer proliferation.
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前列腺癌（PCa）是全球男性癌症发病率和死亡率的主要原因，雄激素信号明显驱动其发病和进展。雄激素受体（AR）的调节是复杂的，仍然难以捉摸，尽管有几项研究解决这些问题。因此，阐明AR调节的潜在机制是抑制PCa的潜在有前途的方法。我们报告说，Par14，脯氨酰异构酶的同源Pin1的一种异构体，是AR转录活性的关键调节器，是必不可少的PCa细胞生长。基于对保藏数据的分析，显示Par14在PCa中过表达。重要的是，Par14的过表达显著增强了雄激素敏感性LNCap细胞的生长。相反，Par14的沉默通过引起细胞周期停滞而显著降低LNCap细胞中的细胞生长。从机制上讲，Par14基因的沉默通过调节p53的定位在mRNA和蛋白质水平上显著诱导细胞周期蛋白依赖性激酶抑制剂p21。此外，在LNCap细胞中抑制Par14被证明在mRNA和蛋白质水平上下调由二氢睾酮诱导的雄激素应答基因的表达。Par14被证明通过其DNA结合结构域直接与细胞核中的AR结合，并增加AR转录活性。因此，Par14在PCa进展中起着关键作用，其对AR信号传导的增强作用可能涉及潜在的分子机制。这些发现表明，Par14是一个有前途的治疗PCa的靶点。脯氨酰异构酶Par14直接与雄激素受体结合。Par14对于细胞增殖及其转录活性是必需的。
Prostate cancer (PCa) is a major cause of cancer morbidity and mortality for men globally, and androgen signaling clearly drives its onset and progression. Androgen receptor (AR) regulation is complex and remains elusive, despite several studies tackling these issues. Therefore, elucidating the mechanism(s) underlying AR regulation is a potentially promising approach to suppressing PCa. We report that Par14, one isoform of the prolyl isomerases homologous to Pin1, is a critical regulator of AR transcriptional activity and is essential for PCa cell growth. Par14 was shown to be overexpressed in PCa, based on analyses of deposited data. Importantly, overexpression of Par14 significantly enhanced androgen‐sensitive LNCap cell growth. In contrast, silencing of Par14 dramatically decreased cell growth in LNCap cells by causing cell cycle arrest. Mechanistically, silencing of the Par14 gene dramatically induced cyclin‐dependent kinase inhibitor p21 at both the mRNA and the protein level through modulating the localization of p53. In addition, suppression of Par14 in LNCap cells was shown to downregulate the expressions of androgen response genes, at both the mRNA and the protein level, induced by dihydrotestosterone. Par14 was shown to directly associate with AR in nuclei via its DNA‐binding domain and augment AR transcriptional activity. Thus, Par14 plays a critical role in PCa progression, and its enhancing effects on AR signaling are likely to be involved in the underlying molecular mechanisms. These findings suggest Par14 to be a promising therapeutic target for PCa. Prolyl isomerase Par14 directly associates with the androgen receptor. Par14 is mandatory for cell proliferation and its transcriptional activity.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
5.9
作者：
Leung JK;Imamura Y;Kato M;Wang J;Mawji NR;Sadar MD
通讯作者：
Sadar MD
影响因子：
6
作者：
Bao, L;Kimzey, A;Wang, DG
通讯作者：
Wang, DG
DOI：
10.1056/nejmoa1315815
发表时间：
2014-09-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Antonarakis ES;Lu C;Wang H;Luber B;Nakazawa M;Roeser JC;Chen Y;Mohammad TA;Chen Y;Fedor HL;Lotan TL;Zheng Q;De Marzo AM;Isaacs JT;Isaacs WB;Nadal R;Paller CJ;Denmeade SR;Carducci MA;Eisenberger MA;Luo J
通讯作者：
Luo J
影响因子：
16.6
作者：
Kuser-Abali G;Alptekin A;Lewis M;Garraway IP;Cinar B
通讯作者：
Cinar B