TRIM68 regulates ligand-dependent transcription of androgen receptor in prostate cancer cells
TRIM68 regulates ligand-dependent transcription of androgen receptor in prostate cancer cells
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DOI：
10.1158/0008-5472.can-07-6059
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发表时间：
2008-05-01
期刊：
影响因子：
11.2
通讯作者：
Hatakeyama, Shigetsugu
中科院分区：
文献类型：
--
作者：
Miyajima, Naoto;Maruyama, Satoru;Hatakeyama, Shigetsugu
雄激素受体（androgen receptor， AR）是核受体家族中介导雄激素作用的转录因子。AR在前列腺的正常发育和前列腺癌的进展中起着重要的作用。AR受几种翻译后修饰调控，包括磷酸化、乙酰化和泛素化。在本研究中，我们发现在前列腺癌细胞中优先表达的E3泛素连接酶TRIM68与AR相互作用，并在双氢睾酮存在下增强AR的转录活性。我们还发现TRIM68与作为AR共激活因子的TIP60和p300在功能上相互作用，并协同作用于AR的反激活。TRIM68在前列腺癌细胞中过表达导致前列腺特异性抗原（PSA）的分泌增加，PSA是前列腺癌最可靠的诊断标志物之一，而TRIM68的敲低会减弱PSA的分泌，抑制细胞生长和集落形成能力。此外，我们发现TRIM68在人前列腺癌中的表达与邻近正常组织中的表达相比显著上调。这些结果表明TRIM68作为ar介导转录的辅助因子，可能成为前列腺癌的一种新的诊断工具和潜在的治疗靶点。
The androgen receptor (AR) is a transcription factor belonging to the family of nuclear receptors that mediate the action of androgen. AR plays an important role in normal development of the prostate, as well as in the progression of prostate cancer. AR is regulated by several posttranslational modifications, including phosphorylation, acetylation, and ubiquitination. In this study, we found that the putative E3 ubiquitin ligase TRIM68, which is preferentially expressed in prostate cancer cells, interacts with AR and enhances transcriptional activity of the AR in the presence of dihydrotestosterone. We also found that TRIM68 functionally interacts with TIP60 and p300, which act as coactivators of AR, and synergizes in the transactivation of AR. Overexpression of TRIM68 in prostate cancer cells caused an increase in secretion of prostate-specific antigen (PSA), one of the most reliable diagnostic markers for prostate cancer, whereas knockdown of TRIM68 attenuated the secretion of PSA and inhibited cell growth and colony-forming ability. Moreover, we showed that TRIM68 expression is sigmficantly up-regulated in human prostate cancers compared with the expression in adjacent normal tissues. These results indicate that TRIM68 functions as a cofactor for AR-mediated transcription and is likely to be a novel diagnostic tool and a potentially therapeutic target for prostate cancer.