Electrophilic Lipid Mediator 15-Deoxy-Δ^12,14-Prostaglandin J₂ Modifies Glucocorticoid Signaling via Receptor SUMOylation

Abstract

Cortisol, the central stress hormone in humans, activates the glucocorticoid receptor (GR). Anti-inflammatory effects are the most important pharmaceutical effects mediated by the GR. Inasmuch as electrophilic cyclopentenone prostaglandin 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) has potent anti-inflammatory properties and activates the SUMOylation pathway, we have investigated the effect of 15d-PGJ₂ on glucocorticoid signaling and receptor SUMOylation. To this end, we studied isogenic HEK293 cells expressing either wild-type GR or SUMOylation-defective GR. Interestingly, 15d-PGJ₂ triggered SUMO-2 and -3 (SUMO-2/3) modification in the primary SUMOylation sites of the GR. Gene expression profiling and pathway analyses indicate that 15d-PGJ₂ inhibits GR signaling in a genome-wide fashion that is significantly dependent on the GR SUMOylation sites. Chromatin immunoprecipitation assays showed that the repressive effect of 15d-PGJ₂ on GR target gene expression occurs in parallel with the inhibition of receptor binding to the target gene chromatin. Furthermore, depletion of UBC9, the sole SUMO E2 conjugase, from HEK293 cells confirmed the involvement of active SUMOylation in the regulatory process. Taken together, our data indicate that GR SUMOylation modulates the glucocorticoid signaling during acute cell stress. Our data also suggest that GR SUMOylation modulates cross talk of the glucocorticoid signaling with other transcription factors that are responsive to cell stress.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00748-14.

ACKNOWLEDGMENTS

We thank Merja Räsänen and Eija Korhonen for assistance with cell cultures and Claude Libert for the TNF-α. We also thank the Finnish Microarray and Sequencing Centre in Turku, Finland, for microarray services.

This work was supported by the Academy of Finland, the Emil Aaltonen Foundation, the North Savo Cancer Foundation, the Kuopio University Foundation, the Finnish Cultural Foundation's North Savo Regional Fund, the UEF Doctoral Programme in Molecular Medicine and the Sigrid Jusélius Foundation, and strategic funding of UEF.