Methylation of TMEM176A, a key ERK signaling regulator, is a novel synthetic lethality marker of ATM inhibitors in human lung cancer

Lay abstract The TMEM176A gene is often methylated in human lung cancer by addition of a methyl group to the gene promotor region. This regulates the expression of TMEM176A. We found that TMEM176A suppressed lung cancer growth both in vitro and in vivo by inhibiting ERK signaling. Methylation of TMEM176A sensitized H1299 and H23 cells to AZD0156, an ATM kinase inhibitor used to induce tumor cell death. Reexpression of TMEM176A reduced the sensitivity of these cells to AZD0156. Methylation of TMEM176A is a novel synthetic lethality therapeutic marker of AZD0156 in human lung cancer. Aim: The role of TMEM176A methylation in lung cancer and its therapeutic application remains unclear. Materials and methods: Nine lung cancer cell lines and 123 cases of cancer tissue samples were employed. Results: TMEM176A was methylated in 53.66% of primary lung cancer. Restoration of TMEM176A expression induced cell apoptosis and G2/M phase arrest, and inhibited colony formation, cell proliferation, migration and invasion. TMEM176A suppressed H1299 cell xenograft growth in mice. Methylation of TMEM176A activated ERK signaling and sensitized H1299 and H23 cells to AZD0156, an ATM inhibitor. Conclusion: The expression of TMEM176A is regulated by promoter region methylation. Methylation of TMEM176A is a potential lung cancer diagnostic marker and a novel synthetic lethal therapeutic marker for AZD0156.