Abstract 1042: Down-regulation of UTX contributes to lung cancer progression

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Smoking, the main risk factor leading to lung cancer, causes both genetic and epigenetic changes resulting in aberrant gene expression. UTX is a histone demethylase that has been implicated in many cancers and has been shown to regulate both cell cycle and differentiation genes. However, the role of UTX has not been elucidated in lung cancer. We hypothesized that smoking injury leads to a down regulation in UTX expression. This results in an inability of repairing airway epithelial cells to differentiate, resulting in premalignant lesions and ultimately invasive lung cancer. Examination of published lung cancer data sets revealed a down-regulation of Utx gene expression in patients with poorer prognosis, tumor grade, tumor recurrence and in smokers. To assess the involvement of UTX protein expression in lung cancer we stained a lung cancer tissue microarray and found a significant correlation between down-regulation of UTX protein expression and poorer prognosis in metastasis (p=0.0005) and smokers (p= 0.02). UTX expression was found to be significantly lower in squamous cell carcinoma compared to adenocarcinoma, linking down-regulation of UTX in a diseased caused solely by smoking. To test if smoking directly affects Utx expression we treated mouse airway epithelial cells at air-liquid interface with media infused with cigarette smoke for 9 days. After this short time point of acute smoke exposure there was a significant down regulation of Utx gene expression (p=0.03). We carried out UTX overexpression studies to assess the role of UTX in lung cancer cells lines and found up-regulation of UTX results in up-regulation of genes involved in lung development and differentiation, including Nrf2, FoxJ2 and FZD4. Our finding support the hypothesis that smoking causes a reduction in UTX that affects the proliferation and differentiation of airway epithelial cells contributing to lung cancer progression. Re-activation of UTX therefore may be a potential therapeutic target for the prevention of lung cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1042. doi:1538-7445.AM2012-1042