TY - JOUR
T1 - Tyrosine phosphorylation regulates ERβ ubiquitination, protein turnover, and inhibition of breast cancer
AU - Yuan, Bin
AU - Cheng, Long
AU - Gupta, Kshama
AU - Chiang, Huai Chin
AU - Gupta, Harshita B.
AU - Sareddy, Gangadhara R.
AU - Wang, Degeng
AU - Lathrop, Kate
AU - Elledge, Richard
AU - Wang, Pei
AU - McHardy, Stanton
AU - Vadlamudi, Ratna
AU - Curiel, Tyler J.
AU - Hu, Yanfen
AU - Ye, Qinong
AU - Li, Rong
PY - 2016/7/5
Y1 - 2016/7/5
N2 - 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.
AB - 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.
KW - ERβ
KW - antitumor activity
KW - protein turnover
KW - tyrosine phosphorylation
KW - ubiquitination
UR - http://www.scopus.com/inward/record.url?scp=85025830426&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.10018
DO - 10.18632/oncotarget.10018
M3 - Article
C2 - 27323858
AN - SCOPUS:85025830426
SN - 1949-2553
VL - 7
SP - 42585
EP - 42597
JO - Oncotarget
JF - Oncotarget
IS - 27
ER -