Montgomery David C, Sorum Alexander W, Guasch Laura, Nicklaus Marc C, Meier Jordan L
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick MD, 21702, USA.
Chem Biol. 2015 Aug 20;22(8):1030-1039. doi: 10.1016/j.chembiol.2015.06.015. Epub 2015 Jul 16.
The finding that chromatin modifications are sensitive to changes in cellular cofactor levels potentially links altered tumor cell metabolism and gene expression. However, the specific enzymes and metabolites that connect these two processes remain obscure. Characterizing these metabolic-epigenetic axes is critical to understanding how metabolism supports signaling in cancer, and developing therapeutic strategies to disrupt this process. Here, we describe a chemical approach to define the metabolic regulation of lysine acetyltransferase (KAT) enzymes. Using a novel chemoproteomic probe, we identify a previously unreported interaction between palmitoyl coenzyme A (palmitoyl-CoA) and KAT enzymes. Further analysis reveals that palmitoyl-CoA is a potent inhibitor of KAT activity and that fatty acyl-CoA precursors reduce cellular histone acetylation levels. These studies implicate fatty acyl-CoAs as endogenous regulators of histone acetylation, and suggest novel strategies for the investigation and metabolic modulation of epigenetic signaling.
染色质修饰对细胞辅因子水平变化敏感这一发现，可能将肿瘤细胞代谢改变与基因表达联系起来。然而，连接这两个过程的特定酶和代谢物仍不清楚。表征这些代谢-表观遗传轴对于理解代谢如何支持癌症信号传导以及开发破坏这一过程的治疗策略至关重要。在此，我们描述了一种化学方法来定义赖氨酸乙酰转移酶（KAT）的代谢调控。使用一种新型化学蛋白质组学探针，我们鉴定出棕榈酰辅酶A（palmitoyl-CoA）与KAT酶之间以前未报道的相互作用。进一步分析表明，棕榈酰辅酶A是KAT活性的有效抑制剂，并且脂肪酰辅酶A前体可降低细胞组蛋白乙酰化水平。这些研究表明脂肪酰辅酶A是组蛋白乙酰化的内源性调节因子，并为表观遗传信号的研究和代谢调节提出了新策略。
