The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Transcriptional regulation of genetic variants in the SLC40A1 promoter

  • Seung Yeon Ha (Department of Pharmacology, Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University) ;
  • Jin-Young Kim (Department of Pharmacology, Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University) ;
  • Ji Ha Choi (Department of Pharmacology, Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University)
  • Received : 2023.10.05
  • Accepted : 2023.12.02
  • Published : 2024.03.01
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Abstract

Solute carrier 40A1 (SLC40A1) encodes ferroportin, which is the only known transmembrane protein that exports elemental iron from mammalian cells and is essential for iron homeostasis. Mutations in SLC40A1 are associated with iron-overload disorders. In addition to ferroportin diseases, SLC40A1 expression is downregulated in various cancer types. Despite the clinical significance of the SLC40A1 transporter, only a few studies have investigated genetic variants in SLC40A1. The present study was performed to identify genetic variations in the SLC40A1 promoter and functionally characterize each variant using in vitro assays. We investigated four haplotypes and five variants in the SLC40A1 promoter. We observed that haplotype 3 (H3) had significantly lower promoter activity than H1, whereas the activity of H4 was significantly higher than that of H1. Luciferase activity of H2 was comparable to that of H1. In addition, four variants of SLC40A1, c.-1355G>C, c.-662C>T, c.-98G>C, and c.-8C>G, showed significantly increased luciferase activity compared to the wild type (WT), whereas c.-750G>A showed significantly decreased luciferase activity compared to the WT. Three transcription factors, cAMP response element-binding protein-1 (CREB-1), chicken ovalbumin upstream promoter transcription factor 1, and hepatic leukemia factor (HLF), were predicted to bind to the promoter regions of SLC40A1 near c.-662C>T, c.-98G>C, and c.-8C>G, respectively. Among these, CREB1 and HLF bound more strongly to the variant sequences than to the WT and functioned as activators of SLC40A1 transcription. Collectively, our findings indicate that the two SLC40A1 promoter haplotypes affect SLC40A1 transcription, which is regulated by CREB-1 and HLF.

Keywords

Acknowledgement

This work was supported by grants from the National Research Foundation of Korea, funded by the Korean government (MSIT) (2020R1A5A2019210 and 2019R1F1A1054449).

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