Long-term exposure to arsenic, esp. the inorganic trivalent arsenic (iAs), a human carcinogen that occurs naturally in the earth's crust or work place due to industrial settings, has been linked to various types of cancers, esp. lung cancer. It has been known for decades that multiple different mechanisms might be involved in iAs-induced malignant transformation. However, whether and how iAs induces cancer stem-like cells (CSCs) from non-stem cells hadn?t been studied. We had previously shown that consecutive treatment of the human bronchial epithelial cells with 0.125 to 0.25 ?M (~9 to 18ppb) iAs for six months induced generation of the CSCs. In addition to the higher expression of the stemness circuit genes, including Oct4, Sox2, myc, Klf4, etc., these iAs-induced CSCs also exhibited a unique metabolic pattern featured with an active glycolysis and diminished mitochondrial oxidative phosphorylation (OXPHOS). ChIP-seq analysis of the parental cells and the iAs-induced CSCs revealed a substantial increase in the enrichment of histone H3 lysine4 trimethylation (H3K4me3), an active epigenetic marker for gene transcription, among genes critical for the stemness and glycolysis of the CSCs. To understand how iAs induces these metabolic and epigenetic changes and the generation of the CSCs, we recently also investigated the capability of iAs on the activation of Nrf2 and HIF1? signaling through both biochemical and ChIP-seq approaches. The data indicate that Nrf2 and HIF1? may serve as initiators for the metabolic and epigenetic reprograming, and the acquisition of the CSC features. Accordingly, we hypothesize that iAs-activated Nrf2 is an upstream activator for HIF1? signaling linked to glycolysis, and the subsequent epigenetic reprogramming and generation of the CSCs. To test this hypothesis, the following three specific aims will be pursued:
Aim1, dissecting Nrf2 activation pathways with an emphasis on the iAs-induced ubiquitination and degradation of Keap1, the endogenous inhibitor of Nrf2;
Aim 2, investigating mechanisms of Nrf2-dependent initiation of HIF1? signaling in the cells in response to iAs;
and Aim 3, understanding how iAs-induced Nrf2-HIF1? signaling shifts the metabolism from mitochondrial TCA cycle to glycolysis that linked to reprogramming of the histone methylation profiles and the generation of CSCs. We expect that the data from the completion of this research plan will be the first to reveal the importance of Nrf2 and HIF1? in iAs- induced CSCs, which may be translated into new strategies of cancer therapy by targeting the Nrf2- HIF1? signaling and the CSCs.

Public Health Relevance

Environmental exposure to carcinogenic metal (metalloid) arsenic, especially the trivalent form, As3+(iAs), has long been a major public health concern. The research proposed in this application is aimed at increasing our understanding of mechanisms by which iAs induces generation of the cancer stem-like cells (CSCs). Main efforts will be on the role of iAs-induced Nrf2-HIF1a signaling linked to glycolysis and the formation of CSCs.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Systemic Injury by Environmental Exposure (SIEE)
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Shaughnessy, Daniel
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Wayne State University
Schools of Pharmacy
United States
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