Here, we test the in vivo role of SETD2 in suppressing KRASG12C-driven tumorigenesis in LUAD, as G12C is the most common KRAS mutation in this tumor type, and identify potential regulatory roles for histone acetylation, particularly H3K27 acetylation, in promoting in vitro methylation of nucleosomes by SETD2. Here, SETD2 is linked to neoplasm.