MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival.
MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival.
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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。
DOI：
10.1101/gad.350736.123
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发表时间：
2023
影响因子：
10.5
通讯作者：
S
中科院分区：
文献类型：
--
作者：
Hurd,Matthew;Pino,Jeffrey;Jang,Kay;Allevato,MichaelM;Vorontchikhina,Marina;Ichikawa,Wataru;Zhao,Yifan;Gates,Ryan;Villalpando,Emily;Hamilton,MichaelJ;Faiola,Francesco;Pan,Songqin;Qi,Yue;Hung,Yu-Wen;Girke,Thomas;Ann,David;S
MYC致癌转录因子被p300和GCN 5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，我们表明，主要的p300-乙酰化K148（149）和K157（158）位点在人类（或小鼠）MYC和主要的GCN 5-乙酰化K323残基可逆乙酰化在各种恶性和非恶性细胞。MYC的致癌性过表达增强了其乙酰化，并改变了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差异地影响其稳定性。赖氨酸至精氨酸的取代表明，虽然没有AcK残基是MYC刺激贴壁细胞增殖所必需的，但单个AcK位点具有控制细胞粘附、接触抑制、细胞凋亡和/或代谢中的选择MYC调节过程的基因特异性功能，并且是MYC的恶性细胞转化活性所必需的。每个AcK位点都是MYC过表达细胞体外非贴壁依赖性生长所必需的，AcK 148（149）和AcK 157（158）残基对于MYC转化细胞体内的致瘤活性也很重要。所确定的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。
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.