Large multicohort study reveals a prostate cancer susceptibility allele at 5p15 regulating TERT via androgen signaling-orchestrated chromatin binding of E2F1 and MYC

Aberrant telomerase reverse transcriptase (TERT) expression is crucial for tumour 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 show that the TERT promoter variant rs2853669 confer risk of prostate cancer (PCa) in different ethnic groups. Further functional investigation reveals that the allele-specific binding of MYC and E2F1 at TERT promoter variant rs2853669 associate with elevated level of TERT in PCa. Mechanistically, androgen stimulations promote the binding of MYC to allele T of rs2853669 thereby activating TERT, whereas hormone deprivations enhance E2F1 binding at allele C of rs2853669, thus upregulate 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 TT and CC genotype of rs2853669 on PCa prognosis and severity. Strikingly, single-nucleotide editing assays showed that 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 provide 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.

异常端粒酶逆转录酶（telomerase reverse transcriptase, TERT）的表达对于肿瘤存活以及癌细胞逃逸细胞凋亡至关重要。研究人员已在5p15染色体区域发现多个与癌症风险相关的TERT基因座变异体，但其潜在作用机制与临床影响仍未明确。本研究通过关联分析证实，TERT启动子变异位点rs2853669在不同种族人群中均与前列腺癌（prostate cancer, PCa）的发病风险相关。进一步的功能实验揭示，MYC与E2F1对TERT启动子rs2853669位点的等位基因特异性结合，与前列腺癌细胞中TERT表达水平升高密切相关。机制层面研究显示，雄激素刺激可促进MYC与rs2853669位点的T等位基因结合，进而激活TERT的转录；而激素剥夺则增强E2F1与该位点C等位基因的结合，从而上调TERT的表达。值得注意的是，E2F1可与雄激素受体（androgen receptor, AR）信号通路协同调控MYC的表达。临床数据表明，MYC/E2F1/TERT的表达水平，或联合rs2853669位点的TT、CC基因型，可对前列腺癌的预后与疾病严重程度产生协同影响。尤为关键的是，单碱基编辑实验证实，rs2853669位点的CC基因型可显著促进上皮间质转化（epithelial-mesenchymal transition, EMT）以及去势抵抗性前列腺癌（castration-resistant PCa, CRPC）的发生发展，该结论通过无偏倚全转录组测序分析得到了验证。本研究结果为理解非编码变异如何协同雄激素信号通路与致癌转录因子，异常调控TERT表达并驱动前列腺癌发生提供了确凿的实验依据。