Reactive oxygen species contribute to arsenic-induced EZH2 phosphorylation in human bronchial epithelial cells and lung cancer cells.

Abstract

Our previous studies suggested that arsenic is able to induce serine 21 phosphorylation of the EZH2 protein through activation of JNK, STAT3, and Akt signaling pathways in the bronchial epithelial cell line, BEAS-2B. In the present report, we further demonstrated that reactive oxygen species (ROS) were involved in the arsenic-induced protein kinase activation that leads to EZH2 phosphorylation. Several lines of evidence supported this notion. First, the pretreatment of the cells with N-acetyl-l-cysteine (NAC), a potent antioxidant, abolishes arsenic-induced EZH2 phosphorylation along with the inhibition of JNK, STAT3, and Akt. Second, H2O2, the most important form of ROS in the cells in response to extracellular stress signals, can induce phosphorylation of the EZH2 protein and the activation of JNK, STAT3, and Akt. By ectopic expression of the myc-tagged EZH2, we additionally identified direct interaction and phosphorylation of the EZH2 protein by Akt in response to arsenic and H2O2. Furthermore, both arsenic and H2O2 were able to induce the translocation of ectopically expressed or endogenous EZH2 from nucleus to cytoplasm. In summary, the data presented in this report indicate that oxidative stress due to ROS generation plays an important role in the arsenic-induced EZH2 phosphorylation.

• Authors: Lingzhi Li, Ping Qiu, Bailing Chen, Yongju Lu, Kai Wu, Chitra Thakur, Qingshan Chang, Jiaying Sun, Fei Chen
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 276 Issue 3 Pg. 165-70 (May 01 2014) ISSN: 1096-0333 [Electronic] United States
• PMID: 24582688 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Reactive Oxygen Species
• Ribosomal Proteins
• ribosomal protein S21
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Polycomb Repressive Complex 2
• Proto-Oncogene Proteins c-akt
• Arsenic

Topics

• Arsenic (toxicity)
• Bronchi (metabolism)
• Cells, Cultured
• Enhancer of Zeste Homolog 2 Protein
• Epithelial Cells (metabolism)
• Humans
• Lung Neoplasms (metabolism)
• Phosphorylation
• Polycomb Repressive Complex 2 (metabolism)
• Protein Transport (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Ribosomal Proteins (metabolism)