Abstract
Trichostatin A (TSA) is an anticancer drug that inhibits histone deacetylases (HDACs). Hypoxia-inducible factor 1 (HIF-1) participates in tumor angiogenesis by upregulating target genes, such as vascular endothelial growth factor (VEGF). In the present study, we investigated whether TSA treatment increases HIF-1α stabilization via acetylation under normoxic conditions, which would lead to VEGF upregulation and resistance to anticancer drugs. TSA enhanced total HIF-1α and VEGF-HRE reporter activity under normoxic conditions. When cells were transfected with GFP-HIF-1α, treatment with TSA increased the number of green fluorescence protein (GFP)-positive cells. TSA also enhanced the nuclear translocation of HIF-1α protein, as assessed by immunoblotting and as evidenced by increased nuclear localization of GFP-HIF-1α. An increase in the interaction between HIF-1α and the VEGF promoter, which was assessed by a chromatin immunoprecipitation (ChIP) assay, led to activation of the VEGF promoter. TSA acetylated HIF-1α at lysine (K) 674, which led to an increase in TSA-induced VEGF-HRE reporter activity. In addition, TSA-mediated cell death was reduced by the overexpression of HIF-1α but it was rescued by transfection with a HIF-1α mutant (K674R). These data demonstrate that HIF-1α may be stabilized and translocated into the nucleus for the activation of VEGF promoter by TSA-mediated acetylation at K674 under normoxic conditions. These findings suggest that HIF-1α acetylation may lead to resistance to anticancer therapeutics, such as HDAC inhibitors, including TSA.
Highlights
The survival rates of tumor patients are decreasing because of tumor cell resistance to anticancer chemotherapies [1]
These data suggest that an increase in vascular endothelial growth factor (VEGF)-hypoxia response element (HRE) reporter activity by Trichostatin A (TSA) might be associated with the binding of HIF-1α to the HRE following nuclear localization of HIF-1α under normoxic conditions
We investigated whether TSA-mediated HIF-1α acetylation affects tumor cell survival via nuclear translocation and binding to the HRE of the VEGF promoter using HeLa cells for the continuation of our previous study [10, 27, 44]
Summary
The survival rates of tumor patients are decreasing because of tumor cell resistance to anticancer chemotherapies [1]. HIF-1α is correlated with vascular density [6, 7], tumor metastasis, angiogenesis, poor patient prognosis, as well as anticancer drug resistance [2]. Anticancer efficacy is reduced by HIF-1α overexpression or hypoxic conditions, which leads to the induction of drug resistance [10, 11]. Tumor hypoxia leads to resistance to radiotherapy [12] It is unknown whether HIF-1α can induce drug resistance of histone deacetylase (HDAC) inhibitor trichostatin A (TSA)
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