G9a methyltransferase governs cell identity in the lung and is required for KRAS G12D tumor development and propagation

Lung development, integrity and repair rely on precise Wnt signaling, which is corrupted in diverse diseases, including cancer. Here, we discover that G9a methyltransferase regulates Wnt signaling in the lung by controlling the transcriptional activity of chromatin-bound β-catenin, through a non-histone substrate. Inhibition of G9a induces transcriptional, morphologic, and molecular changes consistent with alveolar type 2 (AT2) lineage commitment. Mechanistically, G9a activity functions to support regenerative properties of KrasG12D tumors and normal AT2 cells – the predominant cell of origin of this cancer. Consequently, G9a inhibition prevents lung adenocarcinoma tumor formation and propagation,and disrupts normal AT2 cell trans-differentiation. Consistent with these findings, low G9a expression in human lung adenocarcinoma correlates with enhanced AT2 gene expression and improved prognosis. These data reveal G9a as a critical regulator of Wnt signaling, implicating G9a as a potential target in lung cancer and other AT2-mediated lung pathologies.