Elevated expression of Erbin destabilizes ERα protein and promotes tumorigenesis in hepatocellular carcinoma

Background & Aims: Aberrant estrogen receptor-alpha (ER alpha) expression and signaling are implicated in the development of hepatocellular carcinoma (HCC), but its regulation in HCC remains enigmatic. Herein, we aimed to identify a new mechanism by which ER alpha signaling is regulated in HCC, which may lead to a potential new strategy for HCC therapy. Methods: Expression levels of Erbin and ER alpha in human HCC samples were evaluated by immunohistochemistry. In vitro and in vivo experiments were used to assess the effect of Erbin and ER alpha signaling on HCC cell growth. Crosstalk between Erbin and ER alpha signaling was analyzed by molecular methods. Animal models of diethylnitrosamine (DEN) or DEN/CCl4-induced HCC in wild-type Erbin(+/+) and mutant Erbin(Delta C/Delta C) mice were observed. The regulatory effects of Erbin on tamoxifen treatment of HCC were evaluated in vitro and in vivo. Results: Erbin inactivated ER alpha signaling to drive tumorigenesis of HCC, acting to enhance binding of Chip to ER alpha via its interaction with ER alpha and thereby promoting ubiquitination and degradation of ER alpha. Deletion of the PDZ domain of Erbin in Erbin(Delta C/Delta C) mice, disrupted the interaction of Chip and ER alpha, increased the stability of ER alpha protein, and thus inhibited tumorigenesis of HCC. Silencing of Erbin effectively sensitized the response of HCC after tamoxifen treatment in vitro and in vivo. Conclusions: Our data uncovered an important role of Erbin in regulating HCC tumorigenesis through inactivating ER alpha-mediated tumor-suppressive signaling, suggesting a new strategy for tamoxifen therapy in HCC by targeting Erbin/ER alpha signaling axis. Lay summary: Erbin expression is significantly elevated in human hepatocellular carcinoma (HCC) tissue. This elevated expression of Erbin contributes to tumorigenesis of HCC by negatively regulating ER alpha signaling. However, restoring ER alpha signaling by inhibiting Erbin expression enhances the sensitivity of HCC cells to tamoxifen treatment, providing a new approach for tamoxifen treatment in HCC. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.