Metabolic reprogramming, remodeling of the epigenetic landscape, and genomic instability are three processes that drive tumorigenesis. While each has been investigated individually, there is a growing interest in the interplay between each process during early cancer development. High expression of the cystine/glutamate antiporter SLC7A11 (xCT) is frequently seen in lung cancer. Our lab previously demonstrated overexpression of xCT in normal bronchial airway epithelial cells is sufficient to induce metabolic reprogramming. In this study, we investigated the effects of xCT overexpression in normal bronchial airway epithelial cells. We hypothesize that xCT overexpression both induces genomic instability and alters the epigenome in normal bronchial airway epithelial cells through the perturbation of intracellular metabolite levels. Through utilizing an alkaline comet assay, we discovered that xCT overexpression induces DNA damage, increasing the percentage of DNA in the comet tail by 15.1% (P=0.002). Furthermore, we found that xCT overexpression induces alterations to the histone modification landscape, most notably increasing H3K9me3 and H3K9ac by 3.2 and 3.9-fold (P=0.08) respectively. Finally, xCT overexpression shows higher tumorigenic potential through increased colony formation in a soft agar assay. Taken together, xCT overexpression in normal bronchial airway epithelial cells increases tumorigenic potential, induces metabolic reprogramming, causes higher levels of DNA damage, and alters the epigenetic landscape. Future experiments elucidating the links between these processes, including ChIP-seq and whole-genome bisulfite sequencing are currently underway. Establishing causal links between metabolic reprogramming, epigenetic alterations, and genomic instability are imperative in elucidating an effective, potentially multifaceted approach to treating early-stage lung cancer.

Citation Format: Dalton Hill, Jamshedur Rahman, Christien Kluwe, Pierre P. Massion. xCT expression alters the epigenome and induces genomic instability [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-001.