Guangdong Key Laboratory of IoT Information Technology, School of Automation, Guangdong University of Technology, Guangzhou 510006, China.
Faculty of Health Sciences, University of Macau, Macau 999078, China.
Cells. 2019 Jul 10;8(7):698. doi: 10.3390/cells8070698.
Aberrant activation of signaling pathways is frequently observed and reported to be associated with the progression and poor prognosis of prostate cancer (PCa). We aimed to identify key biological processes regulated by androgen receptor (AR) using gene co-expression network from single cell resolution. The bimodal index was used to evaluate whether two subpopulations exist among the single cells. Gene expression among single cells revealed averaging pitfalls and bimodality pattern. Weighted gene co-expression network analysis (WGCNA) was used to identify modules of highly correlated genes. Twenty-nine gene modules were identified and AR-regulated modules were screened by significantly overlapping reported androgen induced differentially expressed genes. The biological function "generation of precursor metabolites and energy" was significantly enriched by AR-regulated modules with bimodality, presenting differential androgen response among subpopulations. Integrating with public ChIP-seq data, two genes FECH, and CROT has AR binding sites. Public in vitro studies also show that androgen regulates FECH and CROT. After receiving androgen deprivation therapy, patients lowly express FECH and CROT. Further survival analysis indicates that FECH/CROT signature can predict PCa recurrence. We reveal the heterogeneous function of "generation of precursor metabolites and energy" upon androgen stimulation from the perspective of single cells. Inhibitors targeting this biological process will facilitate to prevent prostate cancer progression.
信号通路的异常激活经常被观察到，并被报道与前列腺癌（PCa）的进展和预后不良有关。我们旨在使用单细胞分辨率的基因共表达网络来鉴定受雄激素受体（AR）调控的关键生物学过程。双模态指数用于评估单细胞中是否存在两个亚群。单细胞中的基因表达揭示了平均化的缺陷和双峰模式。加权基因共表达网络分析（WGCNA）用于识别高度相关基因的模块。鉴定了 29 个基因模块，并通过显著重叠的报道雄激素诱导的差异表达基因筛选 AR 调控模块。具有双峰性的 AR 调控模块显著富集了“前体代谢物和能量的产生”这一生物学功能，表明亚群之间存在不同的雄激素反应。与公共 ChIP-seq 数据整合后，两个基因 FECH 和 CROT 具有 AR 结合位点。公共体外研究也表明，雄激素调节 FECH 和 CROT。接受雄激素剥夺治疗后，患者低表达 FECH 和 CROT。进一步的生存分析表明，FECH/CROT 特征可以预测 PCa 的复发。我们从单细胞的角度揭示了雄激素刺激下“前体代谢物和能量的产生”的异质性功能。针对该生物学过程的抑制剂将有助于预防前列腺癌的进展。
