Methylation of TMEM176A, a Key ERK Signaling Regulator, is a Novel Synthetic Lethality Marker of ATM Inhibitor in Human Lung Cancer

Background: Synthetic lethality is a new strategy of cancer therapy. Epigenetic based synthetic lethality may provide more opportunities for cancer prevention and treatment. TMEM176A is frequently methylated in esophageal, hepatic and colorectal cancer. The role of TMEM176A methylation in lung cancer and its therapeutic application remains unclear.Methods: Nine lung cancer cell lines and 123 cases of cancer tissue samples were employed. Methylation specific PCR, MTT assay, flow cytometry, and xenograft mouse models were applied.Results: The expression of TMEM176A was found to be regulated by promoter region methylation in lung cancer cells. TMEM176A was methylated in 53.66% (66/123) of primary lung cancer. Reduced expression of TMEM176A was associated with promoter region methylation in 40 cases of matched lung cancer and adjacent tissue samples (P<0.05). No association was found between TMEM176A methylation and age, gender, alcohol abuse, smoking, tumor size, lymph node metastasis, differentiation and TNM stage (all P >0.05). Restoration of TMEM176A expression induced cell apoptosis and G2/M phase arrest and inhibited colony formation, cell proliferation, migration and invasion in H1299 and H23 cells. TMEM176A suppressed H1299 cell xenograft growth in mice. Methylation of TMEM176A activated ERK1/2 signaling, and sensitized H1299 and H23 cells to AZD0156, an ATM inhibitor.Conclusion: TMEM176A is frequently methylated in human lung cancer, and the expression of TMEM176A is regulated by promoter region methylation. TMEM176A suppresses lung cancer growth by inhibiting ERK1/2 signaling. Methylation of TMEM176A is a potential lung cancer diagnostic marker and a novel synthetic lethal therapeutic marker for AZD0156, an ATM inhibitor.