Lung cancer is the most common cause of cancer death in the US and worldwide. Because it has a five-year survival rate of only 18 percent, new therapeutic approaches are urgently needed. We propose to develop novel therapies by targeting the Wnt signaling pathway, which is involved in normal cell growth, but is also implicated in lung cancer development, progression and metastasis. Historically, Wnt signaling has been challenging to target directly, but epigenetic changes that chemically modify DNA or DNA packaging proteins, known as histones, can turn Wnt signaling on or off. In over 80% of lung cancers, the WIF1 protein that normally turns Wnt signaling off, is not produced. We showed that a drug which alters specific modifications to histone 3 restores the production of WIF1, shuts down Wnt expression and induces lung cancer cell death. To advance our observations from bench to bedside, we will 1) determine how specific histone modifications and changes to WIF1 production and Wnt signaling correlate with the disease and its clinical outcomes; 2) analyze the biochemical mechanisms that alter histone modifications to suppress Wnt signaling; and 3) test the effectiveness of two experimental drugs that alter histone modifications to inhibit the tumorigenesis and progression of human lung cancer transplants in mouse models. Successful completion of these studies are expected to unravel important epigenetic pathways that promote Wnt signaling to induce lung cancer, and to identify new drug targets that will suppress Wnt signaling and dramatically improve the outcomes for lung cancer patients.