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

Zhang, Meng ; Sjöström, Martin LU ; Cui, Xiekui ; Foye, Adam ; Farh, Kyle ; Shrestha, Raunak ; Lundberg, Arian ; Dang, Ha X ; Li, Haolong and Febbo, Phillip G , et al. (2024) In Nature Cell Biology 26(7). p.1176-1186
Abstract

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... (More)

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.

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type
Contribution to journal
publication status
published
subject
keywords
Male, Humans, Promoter Regions, Genetic/genetics, Gene Expression Regulation, Neoplastic, Disease Progression, Prostatic Neoplasms/genetics, Receptors, Androgen/metabolism, Hepatocyte Nuclear Factor 3-alpha/metabolism, DNA Methylation, Proto-Oncogene Proteins c-myc/genetics, RNA-Seq, Prostatic Neoplasms, Castration-Resistant/genetics, Cell Line, Tumor
in
Nature Cell Biology
volume
26
issue
7
pages
1176 - 1186
publisher
Nature Publishing Group
external identifiers
  • pmid:38871824
  • scopus:85195841765
ISSN
1465-7392
DOI
10.1038/s41556-024-01438-3
language
English
LU publication?
no
additional info
© 2024. The Author(s), under exclusive licence to Springer Nature Limited.
id
5a5b7009-d9c2-4f07-98d9-52d8c1ed336c
date added to LUP
2026-02-18 08:35:15
date last changed
2026-02-19 04:01:04
@article{5a5b7009-d9c2-4f07-98d9-52d8c1ed336c,
  abstract     = {{<p>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.</p>}},
  author       = {{Zhang, Meng and Sjöström, Martin and Cui, Xiekui and Foye, Adam and Farh, Kyle and Shrestha, Raunak and Lundberg, Arian and Dang, Ha X and Li, Haolong and Febbo, Phillip G and Aggarwal, Rahul and Alumkal, Joshi J and Small, Eric J and Maher, Christopher A and Feng, Felix Y and Quigley, David A}},
  issn         = {{1465-7392}},
  keywords     = {{Male; Humans; Promoter Regions, Genetic/genetics; Gene Expression Regulation, Neoplastic; Disease Progression; Prostatic Neoplasms/genetics; Receptors, Androgen/metabolism; Hepatocyte Nuclear Factor 3-alpha/metabolism; DNA Methylation; Proto-Oncogene Proteins c-myc/genetics; RNA-Seq; Prostatic Neoplasms, Castration-Resistant/genetics; Cell Line, Tumor}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{1176--1186}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Cell Biology}},
  title        = {{Integrative analysis of ultra-deep RNA-seq reveals alternative promoter usage as a mechanism of activating oncogenic programmes during prostate cancer progression}},
  url          = {{http://dx.doi.org/10.1038/s41556-024-01438-3}},
  doi          = {{10.1038/s41556-024-01438-3}},
  volume       = {{26}},
  year         = {{2024}},
}