Human phosphatidylethanolamine-binding protein 4 promotes transactivation of estrogen receptor alpha (ERalpha) in human cancer cells by inhibiting proteasome-dependent ERalpha degradation via association with Src.
We identified human phosphatidylethanolamine-binding protein 4 (hPEBP4) as a human-derived novel member of the phosphatidylethanolamine-binding protein family, which is involved in apoptosis resistance of tumor cells. Because of its preferential expression in estrogen-related cancers, we wondered whether hPEBP4 plays a role in estrogen-induced cancer cell growth. Here, we demonstrated that hPEBP4 inhibited the 17beta-estradiol (E(2))-induced, proteasome-dependent estrogen receptor alpha (ERalpha) degradation to increase the protein level of ERalpha. Silencing of hPEBP4 inhibited the recruitment of ERalpha to the promoter of the ERalpha target gene pS2 in MCF-7 breast cancer cells after E(2) treatment. E(2)-induced, ERalpha-mediated transcription via the estrogen-response element, as well as the cellular proliferation, was significantly suppressed in hPEBP4-silenced MCF-7 cells. We found that Src, whose association with ERalpha facilitates the ERalpha binding to components of proteolytic machinery, could associate with hPEBP4 and that overexpression of hPEBP4 prevented the E(2)-induced interaction between ERalpha and Src. ERalpha overexpression, proteasome inhibitor, or Src inhibitor could reverse the suppression of ERalpha-mediated transactivation by hPEBP4 silencing. The inhibition of the proteasome degradation and the promotion of transactivation of ERalpha by hPEBP4 via the Src pathway were further confirmed in HeLa cells. Finally, we found that the promoting effects of hPEBP4 on ERalpha-mediated transactivation and estrogen-induced proliferation of cancer cells did not depend on its regulation of Akt and ERK activity. Our data suggest that hPEBP4 inhibits proteasome-dependent ERalpha degradation through the Src pathway, thus enhancing ERalpha-mediated transactivation and promoting the proliferation of cancer cells in response to estrogen.
Liu
Haibo
H
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Qiu
Jianming
J
Li
Nan
N
Chen
Taoyong
T
Cao
Xuetao
X
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C518018:PE-binding protein 4, human; D049488:Phosphatidylethanolamine Binding Protein; D011720:Pyrazoles; D011743:Pyrimidines; D004958:Estradiol; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex
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