Intrinsic ubiquitin E3 ligase activity of histone acetyltransferase Hbo1 for estrogen receptor α

Estrogen receptors (ER) are important transcription factors to relay signals from estrogen and to regulate proliferation of some of breast cancers. The cycling of estrogen-induced DNA binding and ubiquitin-linked proteolysis of ER potentiates ER-mediated transcription. Indeed, several transcriptional coactivators for ER-dependent transcription ubiquitinate ER. Histone acetyltransferase (HAT) Hbo1/KAT7/MYST2, involved in global histone acetylation, DNA replication, transcription, and cellular proliferation, promotes proteasome-dependent degradation of ER alpha through ubiquitination. However, molecular mechanism for ubiquitination of ER alpha by Hbo1 is unknown. Here we report the intrinsic ubiquitin E3 ligase activity of Hbo1 toward the ER alpha. The ligand, estradiol-17 beta, inhibited E3 ligase activity of Hbo1 for ER alpha in vitro, whereas hyperactive ER alpha mutants from metastatic breast cancers resistant to hormonal therapy, were better substrates for ER alpha ubiquitination by Hbo1. Hbo1 knock-down caused increase in ER alpha expression. Hbo1 is another ER alpha coactivator that ubiquitinates ER alpha.