An Atlas of Accessible Chromatin in Advanced Prostate Cancer Reveals the Epigenetic Evolution during Tumor Progression
(2024) In Cancer Research 84(18). p.3086-3100- Abstract
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that resists therapy targeting androgen signaling, the primary driver of prostate cancer. mCRPC resists androgen receptor (AR) inhibitors by amplifying AR signaling or by evolving into therapy-resistant subtypes that do not depend on AR. Elucidation of the epigenetic underpinnings of these subtypes could provide important insights into the drivers of therapy resistance. In this study, we produced chromatin accessibility maps linked to the binding of lineage-specific transcription factors (TF) by performing assay for transposase-accessible chromatin sequencing on 70 mCRPC tissue biopsies integrated with transcriptome and whole-genome sequencing. mCRPC had a... (More)
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that resists therapy targeting androgen signaling, the primary driver of prostate cancer. mCRPC resists androgen receptor (AR) inhibitors by amplifying AR signaling or by evolving into therapy-resistant subtypes that do not depend on AR. Elucidation of the epigenetic underpinnings of these subtypes could provide important insights into the drivers of therapy resistance. In this study, we produced chromatin accessibility maps linked to the binding of lineage-specific transcription factors (TF) by performing assay for transposase-accessible chromatin sequencing on 70 mCRPC tissue biopsies integrated with transcriptome and whole-genome sequencing. mCRPC had a distinct global chromatin accessibility profile linked to AR function. Analysis of TF occupancy across accessible chromatin revealed 203 TFs associated with mCRPC subtypes. Notably, ZNF263 was identified as a putative prostate cancer TF with a significant impact on gene activity in the double-negative subtype (AR- neuroendocrine-), potentially activating MYC targets. Overall, this analysis of chromatin accessibility in mCRPC provides valuable insights into epigenetic changes that occur during progression to mCRPC. Significance: Integration of a large cohort of transcriptome, whole-genome, and ATAC sequencing characterizes the chromatin accessibility changes in advanced prostate cancer and identifies therapy-resistant prostate cancer subtype-specific transcription factors that modulate oncogenic programs.
(Less)
- author
- author collaboration
- organization
- publishing date
- 2024-09-16
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Male, Humans, Chromatin/genetics, Prostatic Neoplasms, Castration-Resistant/genetics, Epigenesis, Genetic, Disease Progression, Gene Expression Regulation, Neoplastic, Transcription Factors/genetics, Receptors, Androgen/genetics
- in
- Cancer Research
- volume
- 84
- issue
- 18
- pages
- 3086 - 3100
- publisher
- American Association for Cancer Research Inc.
- external identifiers
-
- scopus:85204257829
- pmid:38990734
- ISSN
- 1538-7445
- DOI
- 10.1158/0008-5472.CAN-24-0890
- language
- English
- LU publication?
- yes
- additional info
- ©2024 American Association for Cancer Research.
- id
- ac0dae41-d713-4459-ad8a-e736061105e5
- date added to LUP
- 2026-02-09 14:29:44
- date last changed
- 2026-02-10 04:02:23
@article{ac0dae41-d713-4459-ad8a-e736061105e5,
abstract = {{<p>Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that resists therapy targeting androgen signaling, the primary driver of prostate cancer. mCRPC resists androgen receptor (AR) inhibitors by amplifying AR signaling or by evolving into therapy-resistant subtypes that do not depend on AR. Elucidation of the epigenetic underpinnings of these subtypes could provide important insights into the drivers of therapy resistance. In this study, we produced chromatin accessibility maps linked to the binding of lineage-specific transcription factors (TF) by performing assay for transposase-accessible chromatin sequencing on 70 mCRPC tissue biopsies integrated with transcriptome and whole-genome sequencing. mCRPC had a distinct global chromatin accessibility profile linked to AR function. Analysis of TF occupancy across accessible chromatin revealed 203 TFs associated with mCRPC subtypes. Notably, ZNF263 was identified as a putative prostate cancer TF with a significant impact on gene activity in the double-negative subtype (AR- neuroendocrine-), potentially activating MYC targets. Overall, this analysis of chromatin accessibility in mCRPC provides valuable insights into epigenetic changes that occur during progression to mCRPC. Significance: Integration of a large cohort of transcriptome, whole-genome, and ATAC sequencing characterizes the chromatin accessibility changes in advanced prostate cancer and identifies therapy-resistant prostate cancer subtype-specific transcription factors that modulate oncogenic programs.</p>}},
author = {{Shrestha, Raunak and Chesner, Lisa N and Zhang, Meng and Zhou, Stanley and Foye, Adam and Lundberg, Arian and Weinstein, Alana S and Sjöström, Martin and Zhu, Xiaolin and Moreno-Rodriguez, Thaidy and Li, Haolong and Alumkal, Joshi J and Aggarwal, Rahul and Small, Eric J and Lupien, Mathieu and Quigley, David A and Feng, Felix Y}},
issn = {{1538-7445}},
keywords = {{Male; Humans; Chromatin/genetics; Prostatic Neoplasms, Castration-Resistant/genetics; Epigenesis, Genetic; Disease Progression; Gene Expression Regulation, Neoplastic; Transcription Factors/genetics; Receptors, Androgen/genetics}},
language = {{eng}},
month = {{09}},
number = {{18}},
pages = {{3086--3100}},
publisher = {{American Association for Cancer Research Inc.}},
series = {{Cancer Research}},
title = {{An Atlas of Accessible Chromatin in Advanced Prostate Cancer Reveals the Epigenetic Evolution during Tumor Progression}},
url = {{http://dx.doi.org/10.1158/0008-5472.CAN-24-0890}},
doi = {{10.1158/0008-5472.CAN-24-0890}},
volume = {{84}},
year = {{2024}},
}