Histone Deacetylase Inhibitor Induced Pvhl-Independent Degradation Of Hif-1 Alpha And Hierarchical Quality Control Of Pvhl Via Chaperone System

The mortality rate of ovarian cancer is increasing and the role of hypoxia inducible factor-1 alpha (HIF-1 alpha) in tumor progression has been confirmed. von Hippel-Lindau tumor suppressor protein (pVHL) binds HIF-1 alpha and mediates proteasome degradation of HIF-1 alpha. Besides, histone deacetylase inhibitor (HDACi) mitigates tumor growth via targeting HIF-1 alpha, whereas underlying mechanism still requires investigation. In this research, we exposed ovarian cancer cell lines OV-90 and SKOV-3 to escalating concentrations of HDACi LBH589. As a result, cell viability was significantly suppressed and expression of HIF-1 alpha was remarkably reduced along with decreased levels of signal molecules, including phosphoinositide 3-kinase (PI3K) and glycogen synthase kinase 3 beta (GSK3 beta) (P = 0.000). Interestingly, pVHL was expressed in a notably declining tendency (P = 0.000). Chaperone heat shock protein-70 (HSP70) was expressed in an ascending manner, whereas expression of chaperonin TCP-1 alpha was reduced clearly (P = 0.000). Besides, co-inhibition of pVHL plus HDAC did not contribute to a remarkable difference in HIF-1 alpha expression as compared with single HDAC inhibition. Furthermore, both cell lines were transfected with plasmids of VHL plus VHL binding protein-1 (VBP-1). Consequently, the expression of HIF-1 alpha as well as lactate dehydrogenase-A (LDHA) was remarkably decreased (P = 0.000). These findings indicate HDACi may repress expression of HIF-1 alpha via inhibiting PI3K and GSK3 beta and promote degradation of HIF-1 alpha via HSP70, independent of pVHL. Additionally, a sophisticated network of HDAC and chaperones may involve in pVHL quality control.