Oncotarget

Research Papers:

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

Bin Yuan, Long Cheng, Kshama Gupta, Huai-Chin Chiang, Harshita B. Gupta, Gangadhara R. Sareddy, Degeng Wang, Kate Lathrop, Richard Elledge, Pei Wang, Stanton McHardy, Ratna Vadlamudi, Tyler J. Curiel, Yanfen Hu, Qinong Ye and Rong Li _

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Oncotarget. 2016; 7:42585-42597. https://doi.org/10.18632/oncotarget.10018

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Abstract

Bin Yuan1,2,3,*, Long Cheng1,*, Kshama Gupta3, Huai-Chin Chiang3, Harshita B. Gupta4, Gangadhara R. Sareddy5, Degeng Wang6,#, Kate Lathrop4, Richard Elledge4, Pei Wang7, Stanton McHardy8, Ratna Vadlamudi5, Tyler J. Curiel4, Yanfen Hu3, Qinong Ye1,2, Rong Li3

1Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, China

2Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Liaoning, China

3Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

4Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

5Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

6Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

7Department of Cellular and Structural Biology Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

8Center for Innovative Drug Discovery, University of Texas at San Antonio, San Antonio, TX, USA

*These authors have contributed equally to this work

#Present address: The Institute of Environmental and Human Health, Texas Tech University, Lubbock, TX, USA

Correspondence to:

Rong Li, email: lir3@uthscsa.edu

Qinong Ye, email: yeqn@nic.bmi.ac.cn

Keywords: tyrosine phosphorylation, ERβ, ubiquitination, antitumor activity, protein turnover

Received: November 22, 2015     Accepted: May 23, 2016     Published: June 14, 2016

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 notion that phosphotyrosine-dependent ERβ signaling is an attractive target for anticancer treatment.


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