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Journal of Biochemistry Advance Access originally published online on September 17, 2008
Journal of Biochemistry 2008 144(5):643-654; doi:10.1093/jb/mvn115
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© 2008 The Japanese Biochemical Society

A Prolyl-hydroxylase Inhibitor, Ethyl-3,4-dihydroxybenzoate, Induces Haem Oxygenase-1 Expression in Human Cells Through a Mechanism Independent of Hypoxia-inducible Factor-1{alpha}

Bin Li, Kazuhisa Takeda*, Satoru Yokoyama{dagger} and Shigeki Shibahara

Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai 980-8575, Japan

*To whom correspondence should be addressed. Tel: +81-22-717-8114; Fax: +81-22-717-8118, E-mail: ktakeda{at}mail.tains.tohoku.ac.jp

Received August 29, 2008; Accepted September 2, 2008


  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-1{alpha}, 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-1{alpha} protein was accumulated in these cell lines. Thus, HIF-1{alpha} 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-1{alpha} protein under normoxia. Treatment with EDHB (250–500 µM) increased HIF-1{alpha} 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-1{alpha}-independent mechanisms.

Key Words: ethyl-3,4-dihydroxybenzoate, haem oxygenase-1, hypoxia, hypoxia-inducible factor-1{alpha}, prolyl-hydroxylase inhibitor

Abbreviations: EDHB ethyl-3, 4-dihydroxybenzoate; HIF-1{alpha}, hypoxia-inducible factor-1{alpha}; HO-1, haem oxygenase-1; HRE, hypoxia-responsive element; MARE, Maf recognition element; Nrf2, NF-E2-related factor-2; RPE, retinal pigment epithelium

{dagger}Present address: Department of Pediatric Oncology, Dana630, Dana-Farber Cancer Institute, 44 Binney St., Boston MA 02115, USA.


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