SIRT6 haploinsufficiency induces BRAFV600E melanoma cell resistance to MAPK inhibitors via IGF signaling

Through integrated transcriptomic, epigenomic and proteomic analyses, we identified IGFBP2, an insulin growth factor (IGF) binding protein, as a direct SIRT6 target gene. We further show that SIRT6 haploinsufficiency, but not complete knock out of SIRT6 promotes IGFBP2 expression via increased H3K56 acetylation at the IGFBP2 locus allowing melanoma cell survival in the presence of MAPK signaling inhibitors (MAPKi). We examine three melanoma cell lines (L-C-B (WT for SIRT6), SIRT6.2-7 (SIRT6 happloinsufficient cells) and SIRT6.1-1 (SIRT6 KO cells)) for transcriptional changes upon MAPK signaling inhibtion to identify SIRT6 targets/pathways whose inhibition might prevent resistance to MAPKi by correlating those with changes in histone modifications at SIRT6 targets