Iizuka Masayoshi, Susa Takao, Tamamori-Adachi Mimi, Okinaga Hiroko, Okazaki Tomoki
Department of Biochemistry, Teikyo University School of Medicine.
Department of Internal Medicine, Teikyo University School of Medicine.
Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(7):498-510. doi: 10.2183/pjab.93.030.
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 ERα through ubiquitination. However, molecular mechanism for ubiquitination of ERα by Hbo1 is unknown. Here we report the intrinsic ubiquitin E3 ligase activity of Hbo1 toward the ERα. The ligand, estradiol-17β, inhibited E3 ligase activity of Hbo1 for ERα in vitro, whereas hyperactive ERα mutants from metastatic breast cancers resistant to hormonal therapy, were better substrates for ERα ubiquitination by Hbo1. Hbo1 knock-down caused increase in ERα expression. Hbo1 is another ERα coactivator that ubiquitinates ERα.
雌激素受体（ER）是重要的转录因子，可传递来自雌激素的信号并调节某些乳腺癌的增殖。雌激素诱导的ER的DNA结合循环和泛素连接的蛋白水解增强了ER介导的转录。实际上，几种用于ER依赖性转录的转录共激活因子会使ER泛素化。参与整体组蛋白乙酰化、DNA复制、转录和细胞增殖的组蛋白乙酰转移酶（HAT）Hbo1/KAT7/MYST2通过泛素化促进蛋白酶体依赖性的ERα降解。然而，Hbo1使ERα泛素化的分子机制尚不清楚。在此我们报道了Hbo1对ERα具有内在的泛素E3连接酶活性。配体17β-雌二醇在体外抑制了Hbo1对ERα的E3连接酶活性，而来自对激素疗法耐药的转移性乳腺癌的高活性ERα突变体是Hbo1使ERα泛素化的更好底物。敲低Hbo1导致ERα表达增加。Hbo1是另一种使ERα泛素化的ERα共激活因子。
