Polyglutamine (polyQ) tract polymorphism within the human androgen receptor (AR) shows population heterogeneity. African American men possess short polyQ tracts significantly more frequently than Caucasian American men. The length of polyQ tracts is inversely correlated with the risk of prostate cancer, age of onset, and aggressiveness at diagnosis. Aberrant activation of Wnt signaling also reveals frequently in advanced prostate cancer, and an enrichment of androgen and Wnt signaling activation has been observed in African American patients. Here, we assessed aberrant expression of AR bearing different polyQ tracts and stabilized β-catenin in prostate tumorigenesis using newly generated mouse models. We observed an early onset oncogenic transformation, accelerated tumor cell growth, and aggressive tumor phenotypes in the compound mice bearing short polyQ tract AR and stabilized β-catenin. RNA sequencing analysis showed a robust enrichment of Myc-regulated downstream genes in tumor samples bearing short polyQ AR versus those with longer polyQ tract AR. Upstream regulator analysis further identified Myc as the top candidate of transcriptional regulators in tumor cells from the above mouse samples with short polyQ tract AR and β-catenin. Chromatin immunoprecipitation analyses revealed increased recruitment of β-catenin and AR on the c-Myc gene regulatory locus in the tumor tissues expressing stabilized β-catenin and shorter polyQ tract AR. These data demonstrate a promotional role of aberrant activation of Wnt/β-catenin in combination with short polyQ AR expression in prostate tumorigenesis and suggest a potential mechanism underlying aggressive prostatic tumor development, which has been frequently observed in African American patients.

人雄激素受体 (AR) 内的聚谷氨酰胺 (polyQ) 束多态性显示出群体异质性。非裔美国男性拥有短 polyQ 束的频率明显高于白人美国男性。polyQ 束的长度与前列腺癌的风险、发病年龄和诊断时的侵袭性呈负相关。Wnt 信号的异常激活也经常出现在晚期前列腺癌中，并且在非洲裔美国患者中观察到雄激素和 Wnt 信号激活的富集。在这里，我们使用新生成的小鼠模型评估了携带不同 polyQ 束和稳定 β-连环蛋白在前列腺肿瘤发生中的异常表达。我们观察到早期发生的致癌转化，加速的肿瘤细胞生长，和具有短 polyQ 束 AR 和稳定 β-连环蛋白的复合小鼠中的侵袭性肿瘤表型。RNA测序分析显示，与具有较长polyQ tract AR的肿瘤样品相比，具有短polyQ AR的肿瘤样品中Myc调节的下游基因的强烈富集。上游调节器分析进一步确定 Myc 是来自上述具有短 polyQ 束 AR 和 β-连环蛋白的小鼠样品中肿瘤细胞中转录调节剂的最佳候选者。染色质免疫沉淀分析显示 β-catenin 和 AR 的募集增加 上游调节器分析进一步确定 Myc 是来自上述具有短 polyQ 束 AR 和 β-连环蛋白的小鼠样品中肿瘤细胞中转录调节剂的最佳候选者。染色质免疫沉淀分析显示 β-catenin 和 AR 的募集增加 上游调节器分析进一步确定 Myc 是来自上述具有短 polyQ 束 AR 和 β-连环蛋白的小鼠样品中肿瘤细胞中转录调节剂的最佳候选者。染色质免疫沉淀分析显示 β-catenin 和 AR 的募集增加肿瘤组织中的c-Myc基因调控位点表达稳定的 β-连环蛋白和较短的 polyQ 束 AR。这些数据证明了 Wnt/β-连环蛋白的异常激活与前列腺肿瘤发生中的短 polyQ AR 表达相结合的促进作用，并提出了侵袭性前列腺肿瘤发展的潜在机制，这在非洲裔美国患者中经常观察到。