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.
Nature cell biology. 2024 Jun 13 [Epub ahead of print]
Meng Zhang, Martin Sjöström, Xiekui Cui, Adam Foye, Kyle Farh, Raunak Shrestha, Arian Lundberg, Ha X Dang, Haolong Li, Phillip G Febbo, Rahul Aggarwal, Joshi J Alumkal, Eric J Small, SU2C/PCF West Coast Prostate Cancer Dream Team , Christopher A Maher, Felix Y Feng, David A Quigley
Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA, USA., Illumina, San Diego, CA, USA., McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA., Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA., Division of Hematology and Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA., Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA. .