Fig. 7: Mechanism of GR-driven, reversible drug-tolerant cancer cell dormancy.

Glucocorticoids act on lung cancer cells by evoking a reversible cell cycle arrest, activating senescence programs, attenuating the metabolic processes, reducing sensitivity to a large array of drugs, inducing dependency towards growth hormone signalling (IGF-1R) and initiating expression of CDKN1C. While GR regulates a large number of genes throughout the genome, we identified that the cell dormancy phenotype is driven by a single GR-target gene, CDKN1C, which encodes for p57, a potent CDK inhibitor protein. This GR target is necessary for the attainment of the cell dormancy phenotype. Regulation of CDKN1C involves a distal enhancer CERES (CDKN1C Enhancer Regulated by Steroids) located upstream of CDKN1C in the KCNQ1 gene, through a GR-induced chromatin looping event. GR and its transcription machinery initiate transcription from the CDKN1C locus, this in turn leads to the acquisition of a cell dormancy phenotype. Crucial for transcriptional activity of GR at CDKN1C locus is the SWI/SNF complex, as its members fine-tune GR transcriptional output allowing for precise control of gene expression. This mechanism of regulation is observed in non-lymphoid solid human cancers, where it contributes to tumour suppression.