RT Journal Article
SR Electronic
T1 Glucocorticoids regulate cancer cell dormancy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 750406
DO 10.1101/750406
A1 Stefan Prekovic
A1 Karianne Schuurman
A1 Anna González Manjón
A1 Mark Buijs
A1 Isabel Mayayo Peralta
A1 Max D. Wellenstein
A1 Seçuk Yavuz
A1 Alejandro Barrera
A1 Kim Monkhorst
A1 Anne Huber
A1 Ben Morris
A1 Cor Lieftink
A1 Joana Silva
A1 Balázs Győrffy
A1 Liesbeth Hoekman
A1 Bram van den Broek
A1 Hans Teunissen
A1 Timothy Reddy
A1 William Faller
A1 Raoderick Beijersbergen
A1 Jos Jonkers
A1 Maarten Altelaar
A1 Karin E. de Visser
A1 Elzo de Wit
A1 Rene Medema
A1 Wilbert Zwart
YR 2019
UL http://biorxiv.org/content/early/2019/09/02/750406.abstract
AB The glucocorticoid receptor directly regulates thousands of genes across the human genome in a cell-type specific manner, governing various aspects of homeostasis. The influence of the glucocorticoid receptor is also seen in various pathologies, including cancer, where it has been linked to tumorigenesis, metastasis, apoptosis resistance, and therapy bypass. Nonetheless, the direct genetic and molecular underpinnings of glucocorticoid action in cancer remain elusive. Here, we dissected the glucocorticoid receptor signalling axis and uncovered the mechanism of glucocorticoid-mediated cancer cell dormancy. Upon glucocorticoid receptor activation cancer cells undergo quiescence, subserved by cell cycle arrest through CDKN1C and reprogramming of signalling orchestrated via FOXO1/IRS2. Strikingly, co-expression of these three genes, directly regulated by glucocorticoid-induced chromatin looping, correlates with a benign molecular phenotype across human cancers, whereas triple loss is associated with increased expression of proliferation/aggressiveness markers. Finally, we show that the glucocorticoid receptor signalling axis is inactivated by alterations of either the chromatin remodelling complex or TP53 in vitro and in vivo. Our results indicate that the activation of the glucocorticoid receptor leads to cancer cell dormancy, which has several implications in terms of glucocorticoid use in cancer therapy.