Tyrosine phosphorylation regulates ERβ ubiquitination, protein turnover, and inhibition of breast cancer

Bin Yuan, Long Cheng, Khama Gupta, Hoai-Chin Chiang, Harshita Gupta, Gangadhara Sareddy, Degeng Wang, Kate Lathrop, Richard Allege, Pei Wang, Stanton McHardy, Ratna Vadlamudi, Tyler J. Curiel, Yanfen Hu, Qinong Ye, Rong Li

Research output: Contribution to journalArticlepeer-review

Abstract

Unlike estrogen receptor α (ERα) that predominantly promotes hormone-dependent breast tumor growth, ERβ exhibits antitumor effects in a variety of cancer types. We recently identified a phosphotyrosine residue in ERβ, but not ERα, that dictates ERβ transcriptional activity and antitumor function. We show here that this ER isotype-specific phosphotyrosine switch is important for regulating ERβ activity in cell proliferation, migration, and invasion. At the mechanistic level, phosphorylated ERβ, which recruits transcriptional coactivator p300, is in turn targeted by p300 for ubiquitination and proteasome-dependent protein turnover. Furthermore, ERβ-specific agonists such as S-equol enhance ERβ phosphorylation, suggesting a crosstalk between ligand- and posttranslational modification-dependent ERβ activation. Inhibition of xenograft tumor growth by S-equol is associated with reduced tumor Ki-67 expression and elevated ERβ tyrosine phosphorylation. Taken together, our data support the not
Original languageEnglish
Pages (from-to)42585-42597
JournalOncotarget
StatePublished - Jul 5 2016

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