Trichostatin A resistance is facilitated by HIF-1α acetylation in HeLa human cervical cancer cells under normoxic conditions
| Autor: | Bo Yeon Kim, Jaewook Lee, Jong Wan Park, Sung Hee Um, Hae Kyoung Han, Dong Hee Yang, Eun-Yi Moon, Sojin Park |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
viruses HIF-1α trichostatin A HeLa 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine drug-resistance Downregulation and upregulation medicine neoplasms acetylation biology organic chemicals Transfection biology.organism_classification normoxic conditions Molecular biology Vascular endothelial growth factor 030104 developmental biology Histone Trichostatin A Oncology chemistry Acetylation 030220 oncology & carcinogenesis biology.protein sense organs Chromatin immunoprecipitation medicine.drug Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|