PXD032041-2

PXD032041 is an original dataset announced via ProteomeXchange.

Title	Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence
Description	In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various stages of the disease. However, therapy resistance inevitably occurs and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multi-omics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from high-risk prostate cancer patients enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors towards a neuroendocrine-like disease state. In addition, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 – from inactive chromatin binding sites towards active cis-regulatory elements that dictate pro-survival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian rhythm core component ARNTL. Post-treatment ARNTL levels associated with poor outcome, and ARNTL suppression decreased cell growth in vitro. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy, and revealed an acquired dependency on circadian regulator ARNTL, a novel candidate therapeutic target.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_07:55:34.740.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Liesbeth Hoekman
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-03 11:56:41	ID requested
1	2022-10-14 14:59:01	announced
⏵ 2	2023-11-14 07:55:37	announced	2023-11-14: Updated project metadata.

submitter keyword: FOXA1, prostate cancer, androgen receptor(AR), enzalutamide,LC-MSMS,ARNTL

Maarten Altelaar
contact affiliation	Proteomics Facility, Netherlands Cancer Institute, Amsterdam, Netherlands. & Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht Institute for Pharmaceutical Sciences, Utrecht University and Netherlands Proteomics Centre, Utrecht, The Netherlands.
contact email	m.altelaar@nki.nl
lab head
Liesbeth Hoekman
contact affiliation	The Netherlands Cancer Institute, Amsterdam, The Netherlands.
contact email	l.hoekman@nki.nl
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/10/PXD032041

PRIDE project URI

• PRIDE
  1. PXD032041
     1. Label: PRIDE project
     2. Name: Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence