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Abstract：
Aberrant telomerase reverse transcriptase (TERT) expression is crucial for tumor survival and cancer cells escaping apoptosis. Multiple TERT-locus variants at 5p15 have been discovered in association with cancer risk, yet the underlying mechanisms and clinical impacts remain unclear. Here, our association studies showed that the TERT promoter variant rs2853669 confers a risk of prostate cancer (PCa) in different ethnic groups. Further functional investigation revealed that the allele-specific binding of MYC and E2F1 at TERT promoter variant rs2853669 associates with elevated level of TERT in PCa. Mechanistically, androgen stimulations promoted the binding of MYC to allele T of rs2853669, thereby activating TERT, whereas hormone deprivations enhanced E2F1 binding at allele C of rs2853669, thus upregulating TERT expression. Notably, E2F1 could cooperate with AR signaling to regulate MYC expression. Clinical data demonstrated synergistic effects of MYC/E2F1/TERT expression or with the TT and CC genotype of rs2853669 on PCa prognosis and severity. Strikingly, single-nucleotide editing assays showed that the CC genotype of rs2853669 obviously promotes epithelial-mesenchymal transition (EMT) and the development of castration-resistant PCa (CRPC), confirmed by unbiased global transcriptome profiling. Our findings thus provided compelling evidence for understanding the roles of noncoding variations coordinated with androgen signaling and oncogenic transcription factors in mis-regulating TERT expression and driving PCa.
摘要：
端粒酶逆转录酶（TERT）的异常表达对于肿瘤存活和癌细胞逃避凋亡至关重要。已发现5p15的多个TERT基因座变异与癌症风险有关，然而潜在的机制和临床影响仍不清楚.这里,我们的关联研究显示,TERT启动子变异体rs2853669在不同种族人群中具有前列腺癌(PCa)的风险.进一步的功能研究表明，在TERT启动子变体rs2853669上，MYC和E2F1的等位基因特异性结合与PCa中TERT水平升高有关。机械上,雄激素刺激促进MYC与rs2853669等位基因T的结合，从而激活TERT，而激素缺乏增强了rs2853669等位基因C上的E2F1结合，从而上调了TERT表达。值得注意的是,E2F1可与AR信号协同调控MYC表达。临床数据表明MYC/E2F1/TERT表达或rs2853669的TT和CC基因型对PCa预后和严重程度的协同作用。引人注目的是，单核苷酸编辑实验表明，rs2853669的CC基因型明显促进上皮间质转化（EMT）和去势抗性PCa（CRPC）的发展，通过无偏全球转录组分析证实。因此，我们的发现为理解与雄激素信号传导和致癌转录因子协调的非编码变异在错误调节TERT表达和驱动PCa中的作用提供了令人信服的证据。
