Acetyl-CoA promotes glioblastoma cell adhesion and migration through Ca2+–NFAT signaling

• DOI: 10.1101/gad.311027.117
• Publication Date: 2018-04-19T15:10:31Z
• Authors: Joyce V. Lee; Corbett T. Berry; Karla Kim; Payel Sen; Taehyong Kim; Alessandro Carrer; Sophie Trefely; Steven Zhao; Sully Fernandez; Lauren E. Barney; Alyssa D. Schwartz; Shelly R. Peyton; Nathaniel W. Snyder; Shelley L. Berger; Bruce D. Freedman; Kathryn E. Wellen
• Keywords: 0301 basic medicine; NFATC Transcription Factors; Mice, Nude; Acetylation; NFAT1; acetyl-CoA; calcium; glioblastoma; histone acetylation; metabolism; ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Acetylation; Animals; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Glioblastoma; Glucose; Histones; Mice, Nude; NFATC Transcription Factors; Calcium Signaling; Cell Adhesion; Cell Movement; Gene Expression Regulation, Neoplastic; Histones; 03 medical and health sciences; Glucose; Acetyl Coenzyme A; Cell Movement; Cell Line, Tumor; ATP Citrate (pro-S)-Lyase; Cell Adhesion; Animals; Female; Calcium Signaling; Glioblastoma; Research Paper

The metabolite acetyl-coenzyme A (acetyl-CoA) is the required acetyl donor for lysine acetylation and thereby links metabolism, signaling, and epigenetics. Nutrient availability alters acetyl-CoA levels in cancer cells, correlating with changes in global histone acetylation and gene expression. However, the specific molecular mechanisms through which acetyl-CoA production impacts gene expression and its functional roles in promoting malignant phenotypes are poorly understood. Here, using histone H3 Lys27 acetylation (H3K27ac) ChIP-seq (chromatin immunoprecipitation [ChIP] coupled with next-generation sequencing) with normalization to an exogenous reference genome (ChIP-Rx), we found that changes in acetyl-CoA abundance trigger site-specific regulation of H3K27ac, correlating with gene expression as opposed to uniformly modulating this mark at all genes. Genes involved in integrin signaling and cell adhesion were identified as acetyl-CoA-responsive in glioblastoma cells, and we demonstrate that ATP citrate lyase (ACLY)-dependent acetyl-CoA production promotes cell migration and adhesion to the extracellular matrix. Mechanistically, the transcription factor NFAT1 (nuclear factor of activated T cells 1) was found to mediate acetyl-CoA-dependent gene regulation and cell adhesion. This occurs through modulation of Ca2+ signals, triggering NFAT1 nuclear translocation when acetyl-CoA is abundant. The findings of this study thus establish that acetyl-CoA impacts H3K27ac at specific loci, correlating with gene expression, and that expression of cell adhesion genes are driven by acetyl-CoA in part through activation of Ca2+–NFAT signaling.