The pluripotency transcription factor NANOG has been implicated in tumor development, and NANOG-expressing cancer cells manifest stem cell properties that sustain tumor homeostasis, mediate therapy resistance and fuel tumor progression. However, how NANOG converges on somatic circuitry to trigger oncogenic reprogramming remains obscure. We previously reported that inducible NANOG expression propels the emergence of aggressive castration-resistant prostate cancer phenotypes. Here we first show that endogenous NANOG is required for the growth of castration-resistant prostate cancer xenografts. Genome-wide chromatin immunoprecipitation sequencing coupled with biochemical assays unexpectedly reveals that NANOG co-occupies a distinctive proportion of androgen receptor/Forkhead box A1 genomic loci and physically interacts with androgen receptor and Forkhead box A1. Integrative analysis of chromatin immunoprecipitation sequencing and time-resolved RNA sequencing demonstrates that NANOG dynamically alters androgen receptor/Forkhead box A1 signaling leading to both repression of androgen receptor-regulated pro-differentiation genes and induction of genes associated with cell cycle, stem cells, cell motility and castration resistance. Our studies reveal global molecular mechanisms whereby NANOG reprograms prostate cancer cells to a clinically relevant castration-resistant stem cell-like state driven by distinct NANOG-regulated gene clusters that correlate with patient survival. Thus, reprogramming factors such as NANOG may converge on and alter lineage-specific master transcription factors broadly in somatic cancers, thereby facilitating malignant disease progression and providing a novel route for therapeutic resistance.

中文翻译：

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NANOG通过动态抑制和接合AR / FOXA1信号轴，将前列腺癌细胞重编程为去势抵抗。

多能性转录因子NANOG与肿瘤发展有关，表达NANOG的癌细胞表现出维持肿瘤稳态，介导治疗抗性并促进肿瘤进展的干细胞特性。然而，NANOG如何在体细胞回路上汇聚以触发致癌基因重编程仍然不清楚。我们先前曾报道，诱导型NANOG表达推动了侵略性去势抵抗性前列腺癌表型的出现。在这里，我们首先显示内源性NANOG是去势抵抗性前列腺癌异种移植物生长所必需的。全基因组染色质免疫沉淀测序与生化分析意外地表明，NANOG共同占据雄激素受体/叉头盒A1基因组基因座的独特比例，并与雄激素受体和叉头盒A1物理相互作用。染色质免疫沉淀测序和时间分辨RNA测序的综合分析表明，NANOG可动态改变雄激素受体/叉头盒A1信号，从而导致雄激素受体调节的前分化基因被抑制，并诱导与细胞周期，干细胞，细胞相关的基因动力和去势抵抗。我们的研究揭示了全球分子机制，其中NANOG将前列腺癌细胞重编程为临床相关的去势抵抗性干细胞样状态，该状态由与患者生存相关的独特NANOG调控基因簇驱动。因此，诸如NANOG的重编程因子可以在体细胞癌中广泛地聚集并改变谱系特异性主转录因子，从而促进恶性疾病的进展并提供治疗耐药性的新途径。