Human Phosphatidylethanolamine-binding Protein 4 Promotes Transactivation of Estrogen Receptor α (ERα) in Human Cancer Cells by Inhibiting Proteasome-dependent ERα Degradation via Association with Src (Publication with Expression of Concern. See vol. 295, pg. 8883, 2020) (Withdrawn Publication. See vol. 296, 2021) (Withdrawn Publication. See vol. 296, 2021)

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 17 beta-estradiol (E-2)- induced, proteasome-dependent estrogen receptor alpha (ER alpha) degradation to increase the protein level of ER alpha. Silencing of hPEBP4 inhibited the recruitment of ER alpha to the promoter of the ER alpha target gene pS2 in MCF-7 breast cancer cells after E-2 treatment. E-2-induced, ER alpha-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 ER alpha facilitates the ER alpha binding to components of proteolytic machinery, could associate with hPEBP4 and that overexpression of hPEBP4 prevented the E2-induced interaction between ER alpha and Src. ER alpha overexpression, proteasome inhibitor, or Src inhibitor could reverse the suppression of ER alpha-mediated transactivation by hPEBP4 silencing. The inhibition of the proteasome degradation and the promotion of transactivation of ER alpha by hPEBP4 via the Src pathway were further confirmed in HeLa cells. Finally, we found that the promoting effects of hPEBP4 on ER alpha-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 ER alpha degradation through the Src pathway, thus enhancing ER alpha-mediated transactivation and promoting the proliferation of cancer cells in response to estrogen.