PXD021924

PXD021924 is an original dataset announced via ProteomeXchange.

Title	Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer
Description	The glucocorticoid receptor (GR) regulates gene expression throughout the human genome in a cell-type-specific manner, governing various aspects of homeostasis. The influence of this transcriptional regulator is seen in multiple pathologies, including cancer. Pharmacological activation of the GR is frequently used to alleviate side-effects caused by therapy for patients with various non-lymphoid solid (i.e. non-hematologic) cancers; however, prior studies have shown that this treatment might also have anti-proliferative action on cancer cells. Nonetheless, the molecular underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the molecular mechanisms of glucocorticoid response in non-lymphoid solid cancers models, focusing on lung cancer. Activation of the GR induces reversible cancer cell dormancy in which cells are tolerant to large array of anti-cancer drugs. This state transition is accompanied by induction of growth factor survival signalling (IGF-1R) and acquired vulnerability to inhibitors of this pathway, both in vitro and in vivo. The observed phenotype is dependent on a single GR target gene - CDKN1C, which encodes for a cell cycle inhibitor protein p57. We have discovered an upstream distal enhancer of CDKN1C, which through GR-induced chromatin looping regulates the expression of this key gene, as confirmed in human tumour specimens. Furthermore, we demonstrate that the SWI/SNF complex composition fine-tunes the GR transcriptional activity at the CDKN1C locus, allowing for precise regulation of cell dormancy induction. Collectively, we show that SWI/SNF-facilitated regulation of CDKN1C underlines GR-induced reversible drug-tolerant state in cancer cells. These insights illustrate the importance of GR signalling in non-lymphoid solid cancer biology, particularly in lung cancer, and warrant caution for use of glucocorticoids in treatment of anti-cancer therapy related side-effects.
HostingRepository	PRIDE
AnnounceDate	2021-05-17
AnnouncementXML	Submission_2021-08-26_04:29:55.001.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	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Q Exactive HF-X; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2020-10-12 06:55:14	ID requested
1	2021-05-17 03:07:37	announced
⏵ 2	2021-08-26 04:29:56	announced	2021-08-26: Updated publication reference for PubMed record(s): 34272384.

Prekovic S, Schuurman K, Mayayo-Peralta I, Manj, ó, n AG, Buijs M, Yavuz S, Wellenstein MD, Barrera A, Monkhorst K, Huber A, Morris B, Lieftink C, Chalkiadakis T, Alkan F, Silva J, Gy, ő, rffy B, Hoekman L, van den Broek B, Teunissen H, Debets DO, Severson T, Jonkers J, Reddy T, de Visser KE, Faller W, Beijersbergen R, Altelaar M, de Wit E, Medema R, Zwart W, Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer. Nat Commun, 12(1):4360(2021) [pubmed]

submitter keyword: Human, LC-MSMS, RIME, LFQ, lung cancer, glucocorticoid receptor, CDKN1C, protein p57, proteome, Phosphoproteome

Maarten Altelaar
contact affiliation	Mass spectrometry/Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 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/2021/05/PXD021924

PRIDE project URI

• PRIDE
  1. PXD021924
     1. Label: PRIDE project
     2. Name: Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer