Histone deacetylase inhibitor SAHA induces ERα degradation in breast cancer MCF-7 cells by CHIP-mediated ubiquitin pathway and inhibits survival signaling

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• 作者：Xin Yi ; Wei Wei ; Sheng-Yu Wang ; Zhi-Yan Du ; Yuan-Ji Xu ; Xiao-Dan Yu
• 关键词：HDACi ; SAHA ; ER ; //www.sciencedirect.com/scidirimg/entities/204e.gif"" alt=""greek small letter alpha"" title=""greek small letter alpha"" border=""0""> ; Breast cancer ; CHIP ; Hsp90
• 刊名：Biochemical Pharmacology
• 出版年：2008
• 出版时间：1 May 2008
• 年：2008
• 卷：75
• 期：9
• 页码：1697-1705
• 全文大小：769 K

文摘

Estrogen receptor (ER) plays an important role in the development and progression of breast cancer, and recent studies showed that ER expression is associated with resistance to hormonal therapy. Therefore, a number of studies have explored ways to deplete ER from breast cancer cells as a new therapy especially for hormone-refractory breast cancer. We reported here that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, effectively depletes ER in breast cancer MCF-7 cells. However, the intrinsic mechanisms by which SAHA decreases ER levels are not clear. Our present data demonstrated that both inhibition of ER mRNA level and promotion of ER degradation by the proteasome contribute to SAHA-induced ER depletion, indicating that SAHA may exert its effects through transcriptional and posttranslational mechanisms. Furthermore, the decrease of ER protein level in MCF-7 cells after SAHA treatment is mainly the result of its rapid degradation by the ubiquitin-proteasome pathway rather than transcriptional inhibition. In addition, we showed that inactivation of the heat shock protein-90 (Hsp90) is involved in SAHA-induced ER degradation, and ubiquitin ligase CHIP (C-terminal Hsc70 interacting protein) enhances SAHA-induced ER degradation. SAHA-induced ER depletion is paralleled with reduction of transcriptional activity of ER and SAHA is able to effectively inhibit cell proliferation and induce apoptosis of MCF-7 cells. Taken together, our results revealed a mechanism for SAHA-induced ER degradation and indicated that SAHA is a suitable pharmacological agent for depletion of ER and a potential choice for breast cancer expressing high ER.