Characterizing the transcriptional signature regulated by the AHR ligands TCDD and kynurenine in colon cancer cells

Abstract

AHR was first identified as the receptor that binds to the pollutant TCDD, which causes tumorigenesis. Since its identification, AHR has been credited to play roles in multiple aspects of carcinogenesis such as increased cellular proliferation, immune evasion, and metastasis. A wide variety of tumors express increased AHR in comparison to the tissue of origin, thus suggesting a positive correlation with tumorigenesis. While most of the research has been focused on the role of activated AHR, a topic that has not received enough attention is whether activation of AHR by different agonists leads to different transcriptional outputs. In this study, we investigated the immediate transcriptional output of colon cancer cell lines exposed to TCDD and Kyn in an AHR‐dependent manner. We found that the expression of CYP1A1, ALDH1A3, ABCG2, ADGFR1, SCIN, and ITPR1 were commonly activated by TCDD, and Kyn, suggesting that these are canonical targets of AHR in colon cancer cells. The activation of expression of CYP1A1, ALDH1A3 and ABCG2 suggests that xenobiotic response pathways are induced upon AHR activation, independent of its ligands. TCDD, which can induce carcinogenesis in various rodent models, induced a larger group of 40 genes, including several potential oncogenes, regulators of cell proliferation, cytoskeletal organization, and signaling. Additionally, we further investigated the effects of SCINin colonic cancer cells. SCINdisrupted proliferation of colon cancer cells when silenced. Gain of function of this gene in colon has not been studied. Our study indicates that this gene can be critical for attachment and activation of the Wnt pathway. Genes activated by AHR are crucial for multiple aspects of carcinogenesis and suggests that targeting AHR by using AHR antagonists could have therapeutic value by limiting cell growth.