TY - JOUR
T1 - Modulation of estrogen related receptor alpha activity by the kinesin KIF17
AU - Seneviratne, A. M.Pramodh Bandara
AU - Turan, Zeynep
AU - Hermant, Aurelie
AU - Lecine, Patrick
AU - Smith, William O.
AU - Borg, Jean Paul
AU - Jaulin, Fanny
AU - Kreitzer, Geri
N1 - Publisher Copyright:
© Seneviratne et al.
PY - 2017/2/7
Y1 - 2017/2/7
N2 - Estrogen-related receptor alpha (ERR1) is an orphan nuclear receptor that can bind transcriptional co-activators constitutively. ERR1 expression correlates with poor patient outcomes in breast cancer, heightening interest in this nuclear receptor as a therapeutic target. Because ERR1 has no known regulatory ligand, a major challenge in targeting its activity is to find cellular or synthetic modulators of its function. We identified an interaction between ERR1 and KIF17, a kinesin-2 family microtubule motor, in a yeast-2-hybrid screen. We confirmed the interaction using in vitro biochemical assays and determined that binding is mediated by the ERR1 ligand-binding/AF2 domain and the KIF17 C-terminal tail. Expression of KIF17 tail domain in either ER-negative or ER-positive breast cancer epithelial cells attenuated nuclear accumulation of newly synthesized ERR1 and inhibited ERR1 transcriptional activity. Conversely, ERR1 transcriptional activity was elevated significantly in KIF17 knock-out cells. Sequence analysis of the KIF17 tail domain revealed it contains a nuclear receptor box with a conserved LXXLL motif found in transcriptional coactivators. Expression of a 12 amino-acid peptide containing this motif was sufficient to inhibit ERR1 transcriptional activity and cell invasion, while deletion of this region from the KIF17 tail resulted in increased ERR1 activity. Together, these data suggest KIF17 modifies ERR1 function by two possible, non-exclusive mechanisms: (i) by regulating nuclear-cytoplasmic distribution or (ii) by competing with transcriptional co-activators for binding to ERR1. Thus targeting the ERR1-KIF17 interaction has potential as a novel strategy for treating breast cancer.
AB - Estrogen-related receptor alpha (ERR1) is an orphan nuclear receptor that can bind transcriptional co-activators constitutively. ERR1 expression correlates with poor patient outcomes in breast cancer, heightening interest in this nuclear receptor as a therapeutic target. Because ERR1 has no known regulatory ligand, a major challenge in targeting its activity is to find cellular or synthetic modulators of its function. We identified an interaction between ERR1 and KIF17, a kinesin-2 family microtubule motor, in a yeast-2-hybrid screen. We confirmed the interaction using in vitro biochemical assays and determined that binding is mediated by the ERR1 ligand-binding/AF2 domain and the KIF17 C-terminal tail. Expression of KIF17 tail domain in either ER-negative or ER-positive breast cancer epithelial cells attenuated nuclear accumulation of newly synthesized ERR1 and inhibited ERR1 transcriptional activity. Conversely, ERR1 transcriptional activity was elevated significantly in KIF17 knock-out cells. Sequence analysis of the KIF17 tail domain revealed it contains a nuclear receptor box with a conserved LXXLL motif found in transcriptional coactivators. Expression of a 12 amino-acid peptide containing this motif was sufficient to inhibit ERR1 transcriptional activity and cell invasion, while deletion of this region from the KIF17 tail resulted in increased ERR1 activity. Together, these data suggest KIF17 modifies ERR1 function by two possible, non-exclusive mechanisms: (i) by regulating nuclear-cytoplasmic distribution or (ii) by competing with transcriptional co-activators for binding to ERR1. Thus targeting the ERR1-KIF17 interaction has potential as a novel strategy for treating breast cancer.
KW - Breast cancer
KW - Epithelial
KW - Estrogen related receptor alpha
KW - Transcription
KW - kinesin
UR - http://www.scopus.com/inward/record.url?scp=85026633554&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.18104
DO - 10.18632/oncotarget.18104
M3 - Article
C2 - 28881568
AN - SCOPUS:85026633554
SN - 1949-2553
VL - 8
SP - 50359
EP - 50375
JO - Oncotarget
JF - Oncotarget
IS - 31
ER -