A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces haem oxygenase-1 expression in human cells through a mechanism independent of hypoxia-inducible factor-1α

Bin Li, Kazuhisa Takeda, Satoru Yokoyama, Shigeki Shibahara

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Hypoxia-inducible factor (HIF)-1 is important for cellular homeostasis under hypoxia. Expression of haem oxygenase-1 (HO-1), an essential enzyme in haem catabolism, varies under hypoxia, depending on cell types. Here, we studied the role of HIF-1α, a component of HIF-1, in the regulation of HO-1 expression using three human cell lines: HeLa cervical cancer, and ARPE-19 and D407 retinal pigment epithelial cells. Under hypoxia (1% O2), the expression of HO-1 mRNA was decreased in HeLa cells, increased in D407 cells, and unchanged in ARPE-19 cells, while HIF-1α protein was accumulated in these cell lines. Thus, HIF-1α is unlikely to function as a key regulator for HO-1 expression under hypoxia. We then used ethyl-3,4-dihydroxybenzoate (EDHB), an inhibitor of prolyl hydroxylases, to accumulate HIF-1α protein under normoxia. Treatment with EDHB (250-500 μM) increased HIF-1α protein levels in HeLa and D407 cells, but not in ARPE-19 cells, whereas EDHB at lower concentrations (50-100 μM) consistently induced HO-1 mRNA expression (about 20-fold) in these three cell lines. Moreover, EDHB increased the HO-1 gene promoter activity via the enhancer that lacks a HIF-1-binding site. In conclusion, the signals evoked by hypoxia and after EDHB treatment differentially regulate HO-1 mRNA expression through HIF-1α-independent mechanisms.

Original languageEnglish
Pages (from-to)643-654
Number of pages12
JournalJournal of biochemistry
Volume144
Issue number5
DOIs
Publication statusPublished - 2008 Nov

Keywords

  • Ethyl-3,4-dihydroxybenzoate
  • Haem oxygenase-1
  • Hypoxia
  • Hypoxia-inducible factor-1α
  • Prolyl-hydroxylase inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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