Histone deacetylase inhibitor induced pVHL-independent degradation of HIF-1α and hierarchical quality control of pVHL via chaperone system.

Jieming Ni,Anping Ni,Gabriele Multhoff

doi:10.1371/journal.pone.0248019

Jieming Ni, Anping Ni + Show 1 more

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https://doi.org/10.1371/journal.pone.0248019

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Abstract

The mortality rate of ovarian cancer is increasing and the role of hypoxia inducible factor-1α (HIF-1α) in tumor progression has been confirmed. von Hippel-Lindau tumor suppressor protein (pVHL) binds HIF-1α and mediates proteasome degradation of HIF-1α. Besides, histone deacetylase inhibitor (HDACi) mitigates tumor growth via targeting HIF-1α, 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-1α was remarkably reduced along with decreased levels of signal molecules, including phosphoinositide 3-kinase (PI3K) and glycogen synthase kinase 3β (GSK3β) (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-1α was reduced clearly (P = 0.000). Besides, co-inhibition of pVHL plus HDAC did not contribute to a remarkable difference in HIF-1α 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-1α as well as lactate dehydrogenase-A (LDHA) was remarkably decreased (P = 0.000). These findings indicate HDACi may repress expression of HIF-1α via inhibiting PI3K and GSK3β and promote degradation of HIF-1α via HSP70, independent of pVHL. Additionally, a sophisticated network of HDAC and chaperones may involve in pVHL quality control.

Highlights

Ovarian cancer has been the eighth most common disease leading to death and the five-year survival rate of patients with ovarian cancer is lower than 45% around the world [1, 2]
We found that histone deacetylase inhibitor (HDACi) repressed Hypoxia inducible factor-1α (HIF-1α) expression via inhibiting phosphoinositide 3-kinase (PI3K) and glycogen synthase kinase 3β (GSK3β) pathway
It is clear that chaperone system including prefoldin VHL binding protein-1 (VBP-1), heat shock protein-70 (HSP70)/90 and TCP1 ring complex (TRiC) is critical in protein homeostasis, and our result interestingly showed a down-regulation of pVHL expression (P = 0.000)

Summary

Introduction

Ovarian cancer has been the eighth most common disease leading to death and the five-year survival rate of patients with ovarian cancer is lower than 45% around the world [1, 2]. Hypoxia inducible factor-1α (HIF-1α) is cellular expression product for hypoxic response due to hyperactive proliferation of tumor, and many studies have proved the correlation between. HIF-1α expression was found with a significantly increased activity on the margin of tumor infiltration and necrosis surroundings and its accumulation in hypoxia further prompts epithelial-mesenchymal transition [7,8,9]. As a crucial metabolic reprogramming factor, HIF-1α may be involved in the progression of a borderline ovarian tumor to an epithelial ovarian cancer, which entails hypoxia-induced invasiveness and migration [10]. The expression of HIF-1α was found to be associated with malignant degree, FIGO stage, lymph node metastasis and overall survival of patients [12, 13]. Activation of phosphoglycerate dehydrogenase in the process of metabolic reprogramming contributes to an increased cellular redox potential, which mitigates efficacy of cytotoxic regimens and enhances resistance [18]

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