Yang Yang,1,* Wei Yin,2,* Fengying Wu,3,* Jiang Fan1 1Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China; 2Key Laboratory of Oral Biomedical Engineering of Ministry of Education, Hospital of Stomatology, School of Stomatology, Wuhan University, Wuhan, China; 3Oncology Department, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China *These authors contributed equally to this work Purpose: This study aims to investigate the possibility of using epigenetic inhibitors against lung cancer. Methods: The changes in the proliferation of human lung cancer cells, NCI-H1975 and NCI-H1299 cells, treated with various doses of inhibitors of DNA methyltransferase (azacitidine [5-AZA]) or histone deacetylase inhibitors (trichostatin A [TSA]) were determined by cell counting. The cell viability of NCI-H1975 and NCI-H1299 cells treated with 5-AZA and/or TSA was measured by the MTT assay. The changes in expression of the AKT signaling pathway molecules caused by the application of 5-AZA and TSA were analyzed through their protein and mRNA levels. A xenograft model was used to observe the effects of 5-AZA and TSA on tumor growth in vivo. Results: 5-AZA and TSA inhibited the proliferation and viability of NCI-H1975 and NCI-H1299 cells. Their joint application significantly influenced the expression of key molecules in AKT signaling pathway in vitro, and inhibited the growth of xenograft tumors in vivo. Furthermore, TSA and 5-AZA decreased the tumorigenic ability of NCI-H1975 cells in vivo. Conclusion: The decreased cell viability and tumorigenic ability, as well as increased anti-oncogene expression following the joint application of 5-AZA and TSA, make these epigenetic inhibitors prospective therapeutic agents for lung cancer. Keywords: lung cancer, epigenetic inhibitor, azacitidine (5-AZA), trichostatin A