Hakai acts as a coregulator of estrogen receptor alpha in breast cancer cells.
Estrogen receptors play a key role in breast cancer development. One of the current therapeutic strategies for the treatment of estrogen receptor (ER)-α-positive breast cancers relies on the blockade of ERα transcriptional activity. In the present study, we characterized Hakai, originally characterized as an E-cadherin binding protein, as a strong blockade of ERα in breast cancer cells. We showed that Hakai inhibited the transcriptional activity of ERα by binding directly to ERα. The DNA-binding domain of ERα was found to be responsible for its interaction with Hakai. Hakai competed with ERα coactivators, such as steroid receptor coactivator-1 (SRC-1) and glucocoriticord receptor interacting protein-1 (GRIP-1), for the modulation of ERα transactivation, while its ubiquitin-ligase activity was not required. Further, overexpression of Hakai inhibited the proliferation and migration of breast cancer cells. Taken together, these results suggest that Hakai is a novel corepressor of ERα and may play a negative role in the development and progression of breast cancers.
Gong
Eun-Yeung
EY
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Korea.
Park
Eunsook
E
Lee
Keesook
K
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3 / Q000235:genetics / Q000378:metabolism; D056918:Nuclear Receptor Coactivators / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D013739:Testosterone / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D047628:Estrogen Receptor alpha; D051958:Nuclear Receptor Coactivator 2; D056918:Nuclear Receptor Coactivators; D013739:Testosterone; D004958:Estradiol; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; C471638:CBLL1 protein, human; D044767:Ubiquitin-Protein Ligases