The two PMTs, G9a/EHMT2 and EZH2 were overexpressed in resistant NSCLC. The two promoted tumour growth and mediated drug resistant in a complementary fashion. Mechanistically, it was revealed that G9a and EZH2 interact and promote the silencing of the tumour-suppressor gene SMAD4, via methylation of H3K9 and K27 at its promoter, which activated the RAF/ERK/c-Myc signalling pathway to mediate resistance in NSCLC. Here, SMAD4 is linked to neoplasm.