OTU Domain-containing Ubiquitin Aldehyde-binding Protein 1 (OTUB1) Deubiquitinates Estrogen Receptor (ER) α and Affects ERα Transcriptional Activity

Estrogen receptor (ER)alpha is an essential component in human physiology and is a key factor involved in the development of breast and endometrial cancers. ER alpha protein levels and transcriptional activity are tightly controlled by the ubiquitin proteasome system. Deubiquitinating enzymes, a class of proteases capable of removing ubiquitin from proteins, are increasingly being seen as key modulators of the ubiquitin proteasome system, regulating protein stability and other functions by countering the actions of ubiquitin ligases. Using mass spectrometry analysis of an ER alpha protein complex, we identified OTU domain containing ubiquitin aldehyde-binding protein 1 (OTUB1) as a novel ER alpha-interacting protein capable of deubiquitinating ER alpha in cells and in vitro. We show that OTUB1 negatively regulates transcription mediated by ER alpha in transient reporter gene assays and transcription mediated by endogenous ER alpha in Ishikawa endometrial cancer cells. We also show that OTUB1 regulates the availability and functional activity of ER alpha in Ishikawa cells by affecting the transcription of the ER alpha gene and by stabilizing the ER alpha protein in the chromatin.