SIRT6 haploinsufficiency induces BRAF^V600E melanoma cell resistance to MAPK inhibitors via IGF signalling.

ABSTRACT: While multiple mechanisms of BRAF^V600-mutant melanoma resistance to targeted MAPK signaling inhibitors (MAPKi) have been reported, the epigenetic regulation of this process remains undetermined. Here, using a CRISPR-Cas9 screen targeting chromatin regulators, we discover that haploinsufficiency of the histone deacetylase SIRT6 allows melanoma cell persistence in the presence of MAPKi. Haploinsufficiency, but not complete loss of SIRT6 promotes IGFBP2 expression via increased chromatin accessibility, H3K56 acetylation at the IGFBP2 locus, and consequent activation of the IGF-1 receptor (IGF-1R) and downstream AKT signaling. Combining a clinically applicable IGF-1Ri with BRAFi overcomes resistance of SIRT6 haploinsufficient melanoma cells in vitro and in vivo. Using matched melano

SUBMITTER: Strub T 

PROVIDER: S-EPMC6109055 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature