Pilot: Center for Appalachian Research in Environmental Sciences: Metabolism-Linked Epigenetic Mechanism in Arsenic Carcinogenesis

Metabolism-linked epigenetic mechanism in arsenic carcinogenesis Exposure to arsenic (As) via drinking water (up to 25 µM) and/or air pollution is of major health concern in USA and worldwide. As a Group I carcinogen, arsenite or As3+ in particular has been implicated as an environmental etiological factor for a number of human cancers, especially lung cancer. Thus, there is an urgent need for a mechanistic understanding of how As exposure leads to lung cancer. There are indications for a pivotal role of cancer stem cells (CSC) in As3+ induced carcinogenesis. Although it is unclear regarding how As exposure is linked to CSC formation, there is emerging evidence that As3+ can induce CSC via metabolic reprogramm ing and epigenetic dysregulation. In this study, we plan to generate compelling preliminary evidence for this hypothesis for future R01 application to NIEHS. Our objective is to map changes in metabolic pathways in CSC- enriched BEAS-2B spheroids derived from a chronic time course treatment (24 wks) of none (Ctl) versus environmentally relevant As3+ (arsenite) concentration (1 µM) and determine relevant metabolic perturbations in As3+-transformed (BAsT) spheroids related to changes in the histone H3 methylation status. We will use our advanced multiplexed Stable Isotope-Resolved Metabolomic (mSIRM) approach to trace central metabolic pathways with emphasis on those implicated in CSC development. We will also employ high-plex, high throughput Reverse Phase Protein Array (RPPA) to profile As3+ transformation-induced changes in a number of metabolic proteins expected to mediate the metabolic perturbations, key CSC stemness markers including their posttranslational modification (PTM) status, key methyl transferases, and histone methylation products H3K4me3, H3K9me3, and H3K27me3 Altogether, these data will enable a strong R01 proposal application to NIEHS. Other matching funds are available to complete the entire study.