Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/27023
Title: Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer.
Austin Authors: Prekovic, Stefan;Schuurman, Karianne;Mayayo-Peralta, Isabel;Manjón, Anna G;Buijs, Mark;Yavuz, Selçuk;Wellenstein, Max D;Barrera, Alejandro;Monkhorst, Kim;Huber, Anne;Morris, Ben;Lieftink, Cor;Chalkiadakis, Theofilos;Alkan, Ferhat;Silva, Joana;Győrffy, Balázs;Hoekman, Liesbeth;van den Broek, Bram;Teunissen, Hans;Debets, Donna O;Severson, Tesa;Jonkers, Jos;Reddy, Timothy;de Visser, Karin E;Faller, William;Beijersbergen, Roderick;Altelaar, Maarten;de Wit, Elzo;Medema, Rene;Zwart, Wilbert
Affiliation: School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia
Semmelweis University Department of Bioinformatics and 2nd Department of Pediatrics, Budapest, Hungary
TTK Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary..
Department of Biostatistics & Bioinformatics, and Centre for Genomic & Computational Biology, Duke University Medical Centre, Durham, NC, USA
Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Division of Cell Biology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Division of Tumour Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Division of Molecular Carcinogenesis and Robotics and Screening Centre, Netherlands Cancer Institute, Amsterdam, The Netherlands
Mass spectrometry/Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Division of Cell Biology and BioImaging Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Division of Gene Regulation, Oncode Institute, 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
Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
Olivia Newton-John Cancer Research Institute
Issue Date: 16-Jul-2021
Date: 2021
Publication information: Nature Communications 2021; 12(1): 4360
Abstract: The 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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/27023
DOI: 10.1038/s41467-021-24537-3
ORCID: 0000-0002-7051-9321
0000-0003-4816-4154
0000-0001-9244-9822
0000-0001-6709-9605
0000-0003-1037-907X
0000-0002-9264-9792
0000-0002-7629-061X
0000-0002-0293-868X
0000-0002-0738-2254
0000-0003-0116-4130
0000-0003-2883-1415
0000-0002-9823-7289
Journal: Nature Communications
PubMed URL: 34272384
Type: Journal Article
Appears in Collections:Journal articles

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