Transcription factor (TF) proteins regulate gene activity by binding to regulatory regions, most importantly at gene promoters. Many genes have alternative promoters (APs) bound by distinct TFs. The role of differential TF activity at APs during tumour development is poorly understood. Here we show, using deep RNA sequencing in 274 biopsies of benign prostate tissue, localized prostate tumours and metastatic castration-resistant prostate cancer, that AP usage increases as tumours progress and APs are responsible for a disproportionate amount of tumour transcriptional activity. Expression of the androgen receptor (AR), the key driver of prostate tumour activity, is correlated with elevated AP usage. We identified AR, FOXA1 and MYC as potential drivers of AP activation. DNA methylation is a likely mechanism for AP activation during tumour progression and lineage plasticity. Our data suggest that prostate tumours activate APs to magnify the transcriptional impact of tumour drivers, including AR and MYC.

转录因子 (TF) 蛋白通过与调节区域（最重要的是基因启动子）结合来调节基因活性。许多基因都有由不同 TF 结合的替代启动子 (AP)。 APs 转录因子活性差异在肿瘤发展过程中的作用尚不清楚。在这里，我们通过对良性前列腺组织、局限性前列腺肿瘤和转移性去势抵抗性前列腺癌的 274 个活检进行深度 RNA 测序，发现随着肿瘤的进展，AP 的使用量会增加，并且 AP 负责不成比例的肿瘤转录活性。雄激素受体 (AR) 的表达是前列腺肿瘤活性的关键驱动因素，与 AP 使用量的增加相关。我们确定 AR、FOXA1 和 MYC 是 AP 激活的潜在驱动因素。 DNA 甲基化是肿瘤进展和谱系可塑性过程中 AP 激活的可能机制。我们的数据表明，前列腺肿瘤激活 AP 来放大肿瘤驱动因素（包括 AR 和 MYC）的转录影响。