Integrative analysis of ultra-deep RNA-seq reveals alternative promoter usage as a mechanism of activating oncogenic programmes during prostate cancer progression.

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.