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

Estrogen receptor α (ERα) plays an important role in the development and progression of breast cancer, and recent studies showed that ERα expression is associated with resistance to hormonal therapy. Therefore, a number of studies have explored ways to deplete ERα 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 ERα in breast cancer MCF-7 cells. However, the intrinsic mechanisms by which SAHA decreases ERα levels are not clear. Our present data demonstrated that both inhibition of ERα mRNA level and promotion of ERα degradation by the proteasome contribute to SAHA-induced ERα depletion, indicating that SAHA may exert its effects through transcriptional and posttranslational mechanisms. Furthermore, the decrease of ERα 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 ERα degradation, and ubiquitin ligase CHIP (C-terminal Hsc70 interacting protein) enhances SAHA-induced ERα degradation. SAHA-induced ERα depletion is paralleled with reduction of transcriptional activity of ERα 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 ERα degradation and indicated that SAHA is a suitable pharmacological agent for depletion of ERα and a potential choice for breast cancer expressing high ERα.