Abstract 1226: The AH receptor plays a key role in mediating IL6 production in head and neck tumor cell lines

Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor conventionally viewed as binding exogenous ligands and mediating gene transcription through DNA binding. Our research has uncovered various structurally distinct ligands, both exogenous and endogenous, that are capable of binding the AHR. We have also recently shown that combinatorial treatment of human breast and cervical cancer cell lines with an AHR ligand and an inflammatory signal results in synergistic induction of interleukin 6 (IL6). Squamous cell cancer of the head and neck is an umbrella term for malignancies developing in numerous locations, including the pharynx, larynx, tongue, and oral cavity. These tumors are often aggressive in nature, with high rates of metastasis to regional lymph nodes. Treatment has historically included radical or modified neck dissection to remove lymph nodes and frequent adjuvant chemotherapy and/or radiation therapy. IL6 production within HNSCC microenvironments both by cancer cells and by tumor-infiltrating macrophages has been shown to correlate with invasive, proliferative, and anti-apoptotic abilities of HNSCC cells, as well as human disease prognosis and recurrence rates. In studying a number of HNSCC cell lines, we have found many to have relatively high basal IL6 production. Using HNSCC2095 as an example, the AHR dependency of basal IL6 production was shown by means of siRNA-mediated AHR knockdown, as well as mediation of basal IL6 transcription following treatment with an AHR antagonist. ChIP assays reveal a significant level of basal AHR occupancy at the IL6 promoter, and antagonist treatment leads to dismissal of the AHR and a combination of coactivators. Similarly, AHR dismissal results in higher occupancy of transcriptional repressors. Key activators lost with AHR dismissal include p65, HDAC3, and BRG1. Following AHR dismissal, an increased presence of dimethylated histone H3 and HDAC1 occurs; both of which are typically repressive. Dismissal of the AHR from the IL6 promoter also leads to a decrease in the IL6-induced STAT3 signaling feedback loop seen in HNSCC lines. Constitutively active STAT3 has been examined as a therapeutic target in HNSCC due to its ability to increase tumor growth and anti-apoptotic effects. Our research shows that AHR binding to the IL6 promoter in HNSCC lines is required for constitutive cytokine production and plays a key role in STAT3 activation. These findings highlight the AHR as a potential target in mediating the autocrine loop of pro-growth signaling in human head and neck cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1226.