Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 17; pp. 5479 - 5484
• Main Authors: Matthews, Laura C., Berry, Andrew A., Morgan, David J., Poolman, Toryn M., Bauer, Kerstin, Kramer, Frederike, Spiller, David G., Richardson, Rachel V., Chapman, Karen E., Farrow, Stuart N., Norman, Michael R., Williamson, Andrew J. K., Whetton, Anthony D., Taylor, Stephen S., Tuckermann, Jan P., White, Michael R. H., Ray, David W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 28.04.2015; National Acad Sciences
• Subjects: anaphase; aneuploidy; Animals; Binding sites; Biological Sciences; Cell division; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Chromosome Segregation; Chromosomes; death; DNA damage; Gene expression; Gene Expression Regulation, Neoplastic; glucocorticoid receptors; Human subjects; Humans; mechanism of action; Mice; Mice, Mutant Strains; mitosis; Mitosis - genetics; neoplasms; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Phosphorylation; Protein Structure, Tertiary; Proteins; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; tissues; Tumor Cells, Cultured; tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; aneuploidy; glucocorticoid receptor; cancer; mitosis; DNA damage
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1411356112

The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily, which controls programs regulating cell proliferation, differentiation, and apoptosis. We have identified an unexpected role for GR in mitosis. We discovered that specifically modified GR species accumulate at the mitotic spindle during mitosis in a distribution that overlaps with Aurora kinases. We found that Aurora A was required to mediate mitosis-driven GR phosphorylation, but not recruitment of GR to the spindle. GR was necessary for mitotic progression, with increased time to complete mitosis, frequency of mitotic aberrations, and death in mitosis observed following GR knockdown. Complementation studies revealed an essential role for the GR ligand-binding domain, but no clear requirement for ligand binding in regulating chromosome segregation. The GR N-terminal domain, and specifically phosphosites S203 and S211, were not required. Reduced GR expression results in a cell cycle phenotype, with isolated cells from mouse and human subjects showing changes in chromosome content over prolonged passage. Furthermore, GR haploinsufficient mice have an increased incidence of tumor formation, and, strikingly, these tumors are further depleted for GR, implying additional GR loss as a consequence of cell transformation. We identified reduced GR expression in a panel of human liver, lung, prostate, colon, and breast cancers. We therefore reveal an unexpected role for the GR in promoting accurate chromosome segregation during mitosis, which is causally linked to tumorigenesis, making GR an authentic tumor suppressor gene. Significance We have discovered a role for the glucocorticoid receptor (GR) in coordinating cell division. We find enrichment of GR to mitotic spindles and demonstrate that GR knockdown causes accumulation of mitotic defects, including delayed anaphase, ternary chromosome segregation, and death in mitosis. Mitotic GR function requires the ligand-binding domain but not ligand binding, revealing a nontranscriptional and ligand-independent mechanism of action. Analysis of GR haploinsufficient cells and tissues reveals increased aneuploidy and DNA damage, and mice show an increased incidence of tumors in vivo, with further GR loss within those incident tumors. We also identify reduced GR expression in several common human cancers, thereby implicating GR as a novel tumor suppressor gene.