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

ABSTRACT: 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).

ORGANISM(S): Homo sapiens

PROVIDER: GSE102813 | GEO | 2018/08/18

REPOSITORIES: GEO

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

Project description:While multiple mechanisms of BRAFV600-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 melanoma samples derived from patients receiving dabrafenib?+?trametinib, we identify IGFBP2 as a potential biomarker for MAPKi resistance. Our study has not only identified an epigenetic mechanism of drug resistance, but also provides insights into a combinatorial therapy that may overcome resistance to standard-of-care therapy for BRAFV600-mutant melanoma patients.

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Project description:The significant increase in the human life-span during the last century confronts us with great medical challenges. To answer them, one must understand and control the mechanisms that determine healthy ageing. The highly conserved sirtuin deacetylases were shown to regulate life-span in lower organisms. Yet, the role of mammalian sirtuins, SIRT1 to 7, in regulating life-span is currently unclear. Here, we show that in SIRT6 transgenic mice (Sirt6-tg), the males but not the females, have a significant increase in life-span. Gene expression analysis revealed significant differences for male Sirt6-tg in comparison to male wild-type mice. Transgenic males display lower serum IGF-1 levels, increased levels of IGFBP-1 and altered phosphorylation levels of major components of the IGF-1 pathway, a key factor in the regulation of life-span. This study is the first to show regulation of mammalian life-span by a sirtuin family member, and has important therapeutic implications for age-related diseases.

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Genome-wide H3K56ac profiling after Sirt6 knockdown in mESCs [ChIP-seq]

Project description:Sirt6, the NAD+-dependent deacetylase, has been described to deacetylate H3K9, H3K18, and H3K56. However, analysis of the acetylation status revealed that loss of Sirt6 caused a massive increase of histone H3K56ac levels but no detectable change of histone H3K9ac and H3K18ac, indicating that SIRT6 is the dominant deacetylase for H3K56ac in muscle stem cells (MuSCs). Further, we investigate genome-wide H3K56ac profiling in the absence of Sirt6 in MuSCs and mouse embryonic stem cells (mESCs) using high throughput sequencing (ChIP-seq).

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Genome-wide H3K56ac profiling after Sirt6 inactivation in MuSCs [ChIP-seq]

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Genome-wide DNA accessibility maps after Sirt6 inactivation in muscle stem cells [ATAC-seq]

Project description:Sirt6, the NAD+-dependent deacetylase, has been described to deacetylate H3K9, H3K18, and H3K56. However, analysis of the acetylation status revealed that loss of Sirt6 caused a massive increase of histone H3K56ac levels but no detectable change of histone H3K9ac and H3K18ac, indicating that SIRT6 is the dominant deacetylase for H3K56ac in muscle stem cells (MuSCs). Further, we investigate genome transposase-accessible chromatin in the absence of Sirt6 in MuSCs using high throughput sequencing (ATAC-seq).

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SIRT6 regulates glucose metabolism and glutamatergic synapse in the mouse retina

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2014-07-30 | E-GEOD-56563 | biostudies-arrayexpress

SIRT6 regulates glucose metabolism and glutamatergic synapse in the mouse retina

2014-07-30 | GSE56563 | GEO

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Expression data from WT SIRT6 and SIRT6 albumin CRE conditional mice

Project description:Microarray analysis of liver tissue from WT SIRT6 and conditional knockout of SIRT6 using albumin-Cre (SIRT6Co/Co ;Alb-Cre) at 2 and 8 months of age RNA was extracted from mouse liver tissue at 2 and 8 months of age. RNA from three pairs of WT SIRT6 and SIRT6Co/Co ;Alb-Cre mice was combined and hybridized to Affymetrix mouse gene 1.0 ST arrays.

2010-06-08 | E-GEOD-21965 | biostudies-arrayexpress

LncPRESS1 is a p53-regulated lncRNA that safeguards pluripotency by disrupting SIRT6 mediated de-acetylation of histone H3K56

Project description:Recent evidence suggests that lncRNAs play an integral regulatory role in numerous functions, including determination of cellular identity. We determined global expression (RNA-seq) and genome wide profiles (ChIP-seq) of histone post-translational modifications and p53 binding in human embryonic stem cells (hESCs) undergoing differentiation to define a high-confidence set of 40 lncRNAs, which are p53 transcriptional targets. We focused on lncRNAs, highly expressed in pluripotent hESCs and repressed by p53 during differentiation, to identify lncPRESS1 as a p53-regulated transcript that maintains hESC pluripotency in concert with core pluripotency factors. RNA-seq of hESCs depleted of lncPRESS1 revealed that lncPRESS1 controls a gene network that promotes pluripotency. Further, we found that lncPRESS1 physically interacts with SIRT6 to prevent SIRT6 chromatin localization and maintain high levels of histone H3K56 and H3K9 acetylation at promoters of pluripotency genes. In summary, we describe a novel pluripotency-specific lncRNA that safeguards the hESC state by disrupting SIRT6 activity

2016-12-07 | GSE76023 | GEO

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