Trichostatin A resistance is facilitated by HIF-1α acetylation in HeLa human cervical cancer cells under normoxic conditions
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Jae-Wook Lee1, Dong Hee Yang1, Sojin Park1, Hae-Kyoung Han1, Jong-Wan Park2, Bo Yeon Kim3, Sung Hee Um4,5 and Eun-Yi Moon1
1Department of Bioscience and Biotechnology, Sejong University, Seoul 05006, South Korea
2Department of Pharmacology, College of Medicine, Seoul National University, Seoul 03080, South Korea
3World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon 28116, South Korea
4Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 16419, South Korea
5Department of Health Sciences and Technology, SAIHST, Samsung Medical Center, Sungkyunkwan University, Seoul 06351, South Korea
Eun-Yi Moon, email: firstname.lastname@example.org
Sung Hee Um, email: email@example.com
Keywords: trichostatin A; HIF-1α; acetylation; drug-resistance; normoxic conditions
Received: January 24, 2017 Accepted: December 08, 2017 Published: December 16, 2017
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.
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