Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer
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Published:2021-07-16
Issue:1
Volume:12
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Prekovic StefanORCID, Schuurman Karianne, Mayayo-Peralta Isabel, Manjón Anna G., Buijs Mark, Yavuz SelçukORCID, Wellenstein Max D., Barrera AlejandroORCID, Monkhorst Kim, Huber Anne, Morris Ben, Lieftink Cor, Chalkiadakis Theofilos, Alkan FerhatORCID, Silva Joana, Győrffy Balázs, Hoekman Liesbeth, van den Broek BramORCID, Teunissen Hans, Debets Donna O., Severson Tesa, Jonkers JosORCID, Reddy TimothyORCID, de Visser Karin E.ORCID, Faller WilliamORCID, Beijersbergen RoderickORCID, Altelaar Maarten, de Wit ElzoORCID, Medema Rene, Zwart WilbertORCID
Abstract
AbstractThe glucocorticoid receptor (GR) regulates gene expression, governing aspects of homeostasis, but is also involved in cancer. Pharmacological GR activation is frequently used to alleviate therapy-related side-effects. While prior studies have shown GR activation might also have anti-proliferative action on tumours, the underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the mechanisms of glucocorticoid response, focusing on lung cancer. We show that GR activation induces reversible cancer cell dormancy characterised by anticancer drug tolerance, and activation of growth factor survival signalling accompanied by vulnerability to inhibitors. GR-induced dormancy is dependent on a single GR-target gene, CDKN1C, regulated through chromatin looping of a GR-occupied upstream distal enhancer in a SWI/SNF-dependent fashion. 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 anticancer therapy related side-effects.
Funder
Nederlandse Organisatie voor Wetenschappelijk Onderzoek KWF Kankerbestrijding
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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