Glucocorticoids regulate cancer cell dormancy

Abstract

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. MainThe Glucocorticoid Receptor (GR) is a member of the nuclear hormone receptor superfamily and a ligand-activated transcription factor 1 . This multidomain protein exerts its function through chromatin binding and communication with the transcriptional machinery, ultimately modulating expression of several hundreds of genes, ubiquitously across diverse cell types 2 . As a homeostatic regulator, GR has an imperative role in neuroendocrine integration, circadian rhythm, immune system control, and glucose metabolism 3 . GR action extends beyond general physiology as its impact can be seen in various disease types, including cancer where it has been linked to tumorigenesis 4 , metastasis 5 , apoptosis resistance 6 , and therapy bypass 7 .As demonstrated using aged mouse haploinsufficiency models, GR loss predisposes to tumour development across multiple organ systems 4 . These findings are further substantiated by studies linking glucocorticoids (GCs) to growth-arrest in cell culture based tumour models 8,9 . Despite the reported influence on tumour biology, the direct genetic and molecular underpinnings of GC-action remain elusive.Herein, we examine the mechanism of GC-regulated cancer cell dormancy, using a multidisciplinary approach to dissect the GR axis and illustrate pathophysiological relevance thereof in human tumours. We show that GR activation leads to acquisition of 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 GC-induced chromatin looping, correlates with a benign...

Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity

“…Importantly, for the majority of primary cancers, GRa was negatively associated with proliferation-related gene signatures (Fig 1E). Among the cancers with most-negative correlation, we observed associations with lung adenocarcinoma (in line with our previous work; Prekovic et al, 2021)…”

“…While systemic glucocorticoid treatment leads to immunosuppression, the implications of GR activity in cancer cells are multifaceted and context dependent. GR can act as both a tumor suppressor and an oncogene, depending on the cancer type or disease stage (Arora et al, 2013;Terwilliger & Abdul-Hay, 2017;Obradovic ´et al, 2019;Prekovic et al, 2021;Mayayo-Peralta et al, 2021b). This poses a potential constraint in terms of cancer treatment and progression.…”

Is the glucocorticoid receptor a key player in prostate cancer?: A literature review

“…In particular, the tumors undergo cell cycle arrest through cyclin-dependent kinase inhibitor 1C and forkhead box O1/insulin receptor substrate 2–orchestrated reprogramming of signaling. [ 47 ] The resulting quiescence slows the tumor proliferation rate. However, quiescent cancer cells can escape conventional antineoplastic treatments.…”

Prognostic Significance of Glucocorticoid Receptor Expression in Cancer: A Systematic Review and Meta-Analysis

“…In other solid tumours, the prognostic role of GR appears to be context and tissue dependent ( Figure 3 and Figure 4 ). Whilst, GR activation is associated with tumour progression and promoting metastasis in solid tumours, a recent BioRxiv preprint reports GR activation also induced tumour dormancy through induction of chromatin looping to regulate cell cycle arrest [ 9 , 71 ]. GR also has a role in cellular transformation as it promotes accurate chromosome segregation during mitosis, independent of ligand binding [ 29 ].…”