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The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer.

机译：作为转录辅助激活剂的雄激素受体：对前列腺癌生长和进展的影响。

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摘要

Prostate cancer depends on the androgen receptor (AR) for growth and survival even in the absence of androgen. In the classical models of gene activation by AR, ligand activated AR signals through binding to the androgen response elements (AREs) in the target gene promoter/enhancer. In the present study the role of AREs in the androgen-independent transcriptional signaling was investigated using LP50 cells, derived from parental LNCaP cells through extended passage in vitro. LP50 cells reflected the signature gene overexpression profile of advanced clinical prostate tumors. The growth of LP50 cells was profoundly dependent on nuclear localized AR but was independent of androgen. Nevertheless, in these cells AR was unable to bind to AREs in the absence of androgen. Gene expression profiling of LP50 cells showed that AR regulates two largely distinct gene expression programs, androgen-dependent and apo-AR dependent. Furthermore, a DNA binding domain mutant of AR which is unable to bind to ARE rescued androgen depletion insensitive proliferation and gene activation in LP50 cells depleted of endogenous wild type AR. Furthermore, ChIP-chip promoter tiling arrays revealed enrichment for AR in chromatin sites that are functional but lack ARE.;To identify candidate transcription factors that tether AR to target genes in the absence of androgen, cis-elements of transcription factors in the AR interactome data set and AR chip peaks were used. We found direct interaction between AR and Elk-1 in both the C81 and C4-2 LNCaP variants of androgen depletion insensitive experimental model systems representing clinical advanced prostate cancer. AR dependent promoter activity of an Elk-1 driven promoter reporter construct and physical association between AR and Elk-1 by coimmunoprecipitation suggested that AR acts as a co-activator of Elk-1. Elk-1 was shown to be necessary for the proliferation of C81 and C4-2 cells. Expression profile studies further showed AR-dependent activation of gene clusters enriched for cell division function by Elk-1. This AR dependent gene regulation by Elk-1 was insensitive to androgen antagonist.;The present study suggests that in advanced prostate cancer AR can support the progression of the tumor through ARE independent mechanisms by acting as a transcriptional co-activator for transcription factors such as Elk-1. This mechanism of action of AR is insensitive to hormone as well as antiandrogen. Hence, therapeutic strategies selectively targeting the interactions between AR and critical tethering proteins could be a novel approach for the management of advanced prostate cancer.
机译：前列腺癌甚至在没有雄激素的情况下也依赖雄激素受体（AR）的生长和存活。在经典的AR基因激活模型中，配体通过与靶基因启动子/增强子中的雄激素响应元件（ARE）结合来激活AR信号。在本研究中，使用LP50细胞研究了ARE在雄激素非依赖性转录信号中的作用，该细胞是通过体外传代从亲本LNCaP细胞获得的。 LP50细胞反映了晚期临床前列腺肿瘤的标志基因过表达特征。 LP50细胞的生长高度依赖于核定位的AR，但不依赖雄激素。然而，在这些细胞中，在没有雄激素的情况下，AR无法与ARE结合。 LP50细胞的基因表达谱表明，AR调节两个很大程度上不同的基因表达程序，雄激素依赖性和apo-AR依赖性。此外，AR的一种DNA结合域突变体不能与ARE结合，从而消除了内源性野生型AR的LP50细胞中雄激素耗竭不敏感的增殖和基因激活。此外，ChIP芯片启动子切片阵列揭示了功能丰富但缺乏ARE的染色质位点中AR的富集;为了鉴定在雄激素不存在的情况下将AR束缚于靶基因的候选转录因子，AR相互作用组中转录因子的顺​​式元件使用数据集和AR芯片峰。我们发现雄激素耗竭不敏感的实验模型系统的C81和C4-2 LNCaP变体中的AR和Elk-1之间存在直接相互作用，代表临床晚期前列腺癌。 Elk-1驱动的启动子报道基因构建体的AR依赖启动子活性以及通过共免疫沉淀在AR和Elk-1之间的物理缔合表明AR充当Elk-1的共激活因子。 Elk-1被证明是C81和C4-2细胞增殖所必需的。表达谱研究进一步表明，Elk-1丰富了细胞分裂功能的基因簇具有AR依赖性激活。 Elk-1对AR的依赖基因调节对雄激素拮抗剂不敏感。；本研究表明，在晚期前列腺癌中，AR可以通过充当ARE的转录共激活因子（例如转录因子）来通过ARE独立机制支持肿瘤的进展。麋鹿1。 AR的这种作用机制对激素以及抗雄激素都不敏感。因此，选择性靶向AR和关键束缚蛋白之间相互作用的治疗策略可能是治疗晚期前列腺癌的新方法。

著录项

  • 作者

    Gonit, Mesfin.;

  • 作者单位

    The University of Toledo.;

  • 授予单位 The University of Toledo.;
  • 学科 Biology Molecular.;Health Sciences Oncology.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 233 p.
  • 总页数 233
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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