Differential transcriptional regulation of hypoxia-inducible factor-1α by arsenite under normoxia and hypoxia: involvement of Nrf2.

Zukaa Al Taleb,Andreas Petry,Thomas Kietzmann,Daniela Mennerich,Agnes Görlach,Elitsa Y Dimova,Tabughang Franklin Chi

doi:10.1007/s00109-016-1439-7

Abstract

Arsenite (As(III)) is widely distributed in nature and can be found in water, food, and air. There is significant evidence that exposure to As(III) is associated with human cancers originated from liver, lung, skin, bladder, kidney, and prostate. Hypoxia plays a role in tumor growth and aggressiveness; adaptation to it is, at least to a large extent, mediated by hypoxia-inducible factor-1α (HIF-1α). In the current study, we investigated As(III) effects on HIF-1α under normoxia and hypoxia in the hepatoma cell line HepG2. We found that As(III) increased HIF-1α protein levels under normoxia while the hypoxia-mediated induction of HIF1α was reduced. Thereby, the As(III) effects on HIF-1α were dependent on both, transcriptional regulation via the transcription factor Nrf2 mediated by NOX4, PI3K/Akt, and ERK1/2 as well as by modulation of HIF-1α protein stability. In line, the different effects of As(III) via participation of HIF-1α and Nrf2 were also seen in tube formation assays with endothelial cells where knockdown of Nrf2 and HIF-1α abolished As(III) effects. Overall, the present study shows that As(III) is a potent inducer of HIF-1α under normoxia but not under hypoxia which may explain, in part, its carcinogenic as well as anti-carcinogenic actions.Key message As(III) increased HIF-1α under normoxia but reduced its hypoxia-dependent induction.The As(III) effects on HIF-1α were dependent on ROS, NOX4, PI3K/Akt, and ERK1/2.The As(III) effects under normoxia involved transcriptional regulation via Nrf2.Knockdown of Nrf2 and HIF-1α abolished As(III) effects in tube formation assays.The data may partially explain As(III)’s carcinogenic and anti-carcinogenic actions.

Highlights

Several regions in Argentina, Canada, India, Japan, China, Taiwan, Mexico, Chile, and the USA are characterized by the presence of inorganic arsenic as natural contaminant in drinking water
In order to gain a better understanding about the mechanisms and actions involved when cells are exposed to arsenite, we focused in the current study on the impact of arsenite on hypoxia-inducible factor-1α (HIF-1α) regulation under normoxia and hypoxia
We found that arsenite induced the levels of hypoxia-inducible factor (HIF)-1α under normoxia via a transcriptional mechanism involving NADPH oxidase-generated reactive oxygen species (ROS), the phosphatidylinositol 3-kinase (PI3K)/Akt and ERK1/2 pathway, and the redox-dependent transcription factor Nrf2

Summary

Introduction

Several regions in Argentina, Canada, India, Japan, China, Taiwan, Mexico, Chile, and the USA are characterized by the presence of inorganic arsenic as natural contaminant in drinking water. This implies that more than 100 million persons are chronically exposed to inorganic arsenic at levels higher than the maximum contaminant level of 0.13 μmol/l set by the WHO [1]. A prerequisite for the formation of the HIF-1 heterodimer is the hypoxia-dependent stabilization of the HIF-1α subunit and the recruitment of coactivators This is primarily achieved at the post-translational level by hydroxylation events occurring at the N-terminal (N-TAD) and Cterminal (C-TAD) transactivation domain of HIF-1α [7,8,9]. HIF-1α is responsive to a variety of non-hypoxic stimuli among them transition metals such as CoCl2, chromium, or arsenite (for review, see [14, 15])

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Conclusion