The MYC oncogenic transcription factor is acetylated by the p300 and GCN5 histone acetyltransferases. The significance of MYC acetylation and the functions of specific acetylated lysine (AcK) residues have remained unclear. Here, we show that the major p300-acetylated K148(149) and K157(158) sites in human (or mouse) MYC and the main GCN5-acetylated K323 residue are reversibly acetylated in various malignant and nonmalignant cells. Oncogenic overexpression of MYC enhances its acetylation and alters the regulation of site-specific acetylation by proteasome and deacetylase inhibitors. Acetylation of MYC at different K residues differentially affects its stability in a cell type-dependent manner. Lysine-to-arginine substitutions indicate that although none of the AcK residues is required for MYC stimulation of adherent cell proliferation, individual AcK sites have gene-specific functions controlling select MYC-regulated processes in cell adhesion, contact inhibition, apoptosis, and/or metabolism and are required for the malignant cell transformation activity of MYC. Each AcK site is required for anchorage-independent growth of MYC-overexpressing cells in vitro, and both the AcK148(149) and AcK157(158) residues are also important for the tumorigenic activity of MYC transformed cells in vivo. The MYC AcK site-specific signaling pathways identified may offer new avenues for selective therapeutic targeting of MYC oncogenic activities.

中文翻译：

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MYC 乙酰化赖氨酸残基驱动致癌细胞转化并调节细胞粘附独立生长和存活的选择遗传程序

MYC 致癌转录因子被 p300 和 GCN5 组蛋白乙酰转移酶乙酰化。MYC 乙酰化的意义和特定乙酰化赖氨酸 (AcK) 残基的功能仍不清楚。在这里，我们发现人（或小鼠）MYC 中主要的 p300 乙酰化 K148(149) 和 K157(158) 位点以及主要 GCN5 乙酰化 K323 残基在各种恶性和非恶性细胞中发生可逆乙酰化。MYC 的致癌性过度表达会增强其乙酰化，并改变蛋白酶体和脱乙酰酶抑制剂对位点特异性乙酰化的调节。MYC 在不同 K 残基处的乙酰化以细胞类型依赖性方式不同地影响其稳定性。赖氨酸到精氨酸的取代表明，虽然 MYC 刺激贴壁细胞增殖不需要任何 AcK 残基，但各个 AcK 位点具有基因特异性功能，控制细胞粘附、接触抑制、细胞凋亡和/或代谢并且是 MYC 恶性细胞转化活性所必需的。每个 AcK 位点对于 MYC 过表达细胞的体外贴壁依赖性生长都是必需的，AcK148(149) 和 AcK157(158) 残基对于体内 MYC 转化细胞的致瘤活性也很重要。确定的 MYC AcK 位点特异性信号通路可能为 MYC 致癌活性的选择性治疗靶向提供新途径。