Chromatin, Gene, and RNA Regulation MYC-Induced Epigenetic Activation of GATA4 in Lung Adenocarcinoma

Human lung cancer is a disease with high incidence and accounts formost cancer-related deaths in bothmen and women.Metastasis is a common event in non–small cell lung carcinoma (NSCLC), diminishing the survival chance of the patients with this type of tumor. It has been shown that MYC is involved in the development of metastasis fromNSCLC, but themechanism underlying this switch remained to be identified. Here, we focus onGATA4 as a MYC target in the development of metastasis with origin in lung adenocarcinoma, the most common type of NSCLC. Epigenetic alterations at the GATA4 promoter level were observed after MYC expression in lung adenocarcinoma in vivo and in vitro. Such alterations include site-specific demethylation that accompanies the displacement of theMYC-associated zinc finger protein (MAZ) from theGATA4 promoter, which leads toGATA4 expression. Histone modification analysis of theGATA4 promoter revealed a switch from repressive histone marks to active histone marks after MYC binding, which corresponds to active GATA4 expression. Our results thus identify a novel epigenetic mechanism by which MYC activates GATA4 leading to metastasis in lung adenocarcinoma, suggesting novel potential targets for the development of antimetastatic therapy.Mol Cancer Res; 11(2); 161–72. 2012 AACR.