Emerging roles of the ubiquitin-proteasome system in the steroid receptor signaling

The ubiquitin-proteasome system (UPS) harbors elaborated protein quality control systems in eukaryotic cells. Recently, the UPS is emerging as an important regulator in controlling the magnitude and the duration of the steroid hormone responses. Upon steroid hormone stimuli, their cognate steroid receptors, including androgen receptor (AR) and estrogen receptor (ER), not only mediate transcriptional activation, but also undergo ubiquitination and consequent proteasomal degradation. Many reports have strongly suggested that UPS machinery, particularly the E3 ubiquitin ligases, are closely involved in the receptor-mediated gene expression regulation. Both ligand-dependent and -independent recruitment of E3 ubiquitin ligases often prompt the degradation of target steroid receptors and correct transcription activation. Here, we review that the deep mechanistic connections between AR and ER-dependent transcription and the UPS for the correct expression of target genes. We also emphasize that this regulatory system has a significant potential for future clinical application, including the treatment of breast and prostate cancers by facilitating the degradation of related hormone receptors.