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
Authors: Haibo Liu
Jianming Qiu
Nan Li
Xuetao Cao
Taoyong Chen
Journal: Journal of Biological Chemistry (2010)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: hPEBP4; apoptosis resistance; tumor cells; estrogen-related cancers; ERalpha degradation
Affiliations: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.

Abstract:  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. 

Retracted: No

PubPeer comments:
 2020 Expression of Concern. https: www.jbc.org content 295 26 8883 The publisher of the Journal of Biological Chemistry is issuing an Expression of Concern to inform readers that credible concerns have been raised regarding some of the data and conclusions in the article listed above. The Journal of Biological Chemistry will provide additional information as it becomes available. , 
 1 1 2021  VOLUME 285 (2010) PAGES 21934u201321942 This article has been withdrawn by the authors. The Journal states that in Fig. 4C, the bottom immunoblot contains a splice before the IgG lane and the IgG lane contains no data. There is also inappropriate image manipulation in Fig. 5B in the Src panel immunoblot. The authors provided the original raw data image for Fig. 4C and state that it was a labeling mistake. The authors state that they disagree with the Journalu2019s findings in Fig. 5B. The authors offer to correct the labeling mistake and replace the images in question with those from experiments under the same conditions. The Journal declined the offer. This article reported the functional characterization of a novel molecule the authors discovered. The authors state that the issues described above do not affect the interpretation of the data nor conclusions of this research study. The authors have indicated that they plan to submit this work elsewhere for publication. , 
 A post-mortem analysis of Figure 4C (red arrow points to the missing data in the IgG lane) and Figure 5B (a blue arrow points out a possible splice). ![file] ,