ATPS-96HISTONE DEACETYLASE INHIBITORS REPRESS HYPOXIA SIGNALING THROUGH AFFECTING HSP90

Abstract

Histone deacetylase inhibitors (HDACis) are among the most promising recently developed anti-cancer agents. Recent work suggests that HDACis suppress both malignant cell metabolism and progression by interfering with the hypoxia-inducible factor (HIF) signaling, which plays a key role in tumor progression in both actual and falsely perceived cellular hypoxia (pseudohypoxia). However, the precise biochemical mechanism of HDACis repression of HIFs function remains unclear. In this study, we demonstrated that the class-2 histone deacetylase inhibitor SAHA potently inhibits hypoxia signaling via interfering with heat shock protein 90 (Hsp90). HDACis increase in the acetylation of Hsp90, resulting in less HIF-a recognition and nuclear translocation. Accumulated cytoplasmic HIF-a is not transcriptional active and degradaded through proteosomal pathway. Finally, we demonstrated that SAHA remarkably reduce hypoxia signaling and decrease tumor growth in vivo. These findings provide insight into new possible therapeutic strategies for using HDACis in tumors with known HIF pathway aberrations.