Cell cycle-coupled expansion of AR activity promotes cancer progression.
Cell cycle-coupled expansion of AR activity promotes cancer progression.
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DOI：
10.1038/onc.2016.334
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发表时间：
2017-03-23
期刊：
影响因子：
8
通讯作者：
Knudsen KE
中科院分区：
文献类型：
--
作者：
McNair C;Urbanucci A;Comstock CE;Augello MA;Goodwin JF;Launchbury R;Zhao SG;Schiewer MJ;Ertel A;Karnes J;Davicioni E;Wang L;Wang Q;Mills IG;Feng FY;Li W;Carroll JS;Knudsen KE
雄激素受体(AR)是前列腺癌(PCa)生存和发展所必需的，而去除AR活性是治疗播散性疾病的一线措施。虽然最初有效，但复发的肿瘤最终会出现，没有持久的治疗方法。尽管PCa在整个疾病过程中依赖于AR的活性，但控制疾病进展的AR依赖的转录网络仍然难以描绘，AR在有丝分裂活跃细胞中的功能也不是很清楚。分析AR活性作为细胞周期的函数，揭示了在活跃的细胞周期中AR调节基因网络的一个意想不到的和高度扩展的谱系。新的AR功能被分成两个主要的簇：那些专用于周期细胞并在有丝分裂细胞周期中保留的功能(“细胞周期共同”)，与那些在细胞周期的一个子集中特别丰富的功能(“时相限制”)。进一步的分析发现，在与临床前列腺癌进展相关的主要通路中，以前未被识别的AR功能。二氢神经酰胺去饱和酶1(DEGS1)被证实是促进前转移表型的有丝分裂活性细胞中的AR调节基因，在晚期PCa中被证明与转移的发生、治疗干预后的复发和总体生存率的降低高度相关，这说明了这些未被掩盖的AR驱动的通路的影响。综上所述，这些发现描绘了有丝分裂活跃的肿瘤细胞中的AR功能，从而为AR促进致死性前列腺癌的发生提供了重要的分子基础，并为治疗干预提供了新的途径。
The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle (“Cell Cycle Common”), versus those that were specifically enriched in a subset of cell cycle phases (“Phase Restricted”). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide-desaturase 1 (DEGS1) was identified as an AR regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention, and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.