DOT1L O-GlcNAcylation promotes its protein stability and MLL-fusion leukemia cell proliferation
DOT1L O-GlcNAcylation promotes its protein stability and MLL-fusion leukemia cell proliferation
复制标题
DOT1L O-GlcNAcylation 促进其蛋白质稳定性和 MLL 融合白血病细胞增殖
DOI：
10.1016/j.celrep.2021.109739
复制
发表时间：
2021-09-21
期刊：
影响因子：
8.8
通讯作者：
Sun, Lidong
中科院分区：
文献类型：
--
作者：
Song, Tanjing;Zou, Qingli;Sun, Lidong
组蛋白赖氨酸甲基化在细胞外环境和细胞内基因表达的界面上的功能。 DOT1L是一种多功能的组蛋白H3K79甲基转移酶，在MLL融合白血病中起着重要作用，但对于DOT1L如何反应细胞外刺激。在这里，我们报告说，DOT1L蛋白的稳定性受六胺生物合成途径（HBP）的细胞外葡萄糖水平调节。从机械上讲，DOT1L在其C末端的进化保守的S1511处被O-GlcNacyLeL。我们将ube3c识别为dot1l E3泛素连接酶促进dot1l降解，其与dot1l的相互作用易受o-glcnacylation的相互作用。因此，HBP增强了H3K79甲基化和临界DOT1L靶基因（例如HOXA9/MEIS1）的表达，从而促进了MLL融合性白血病中的细胞增殖。抑制HBP或O-GLCNAC转移酶（OGT）会增加细胞对DOT1L抑制剂的敏感性。总体而言，我们的工作将O-Glcnacylation和UBE3C视为DOT1L蛋白丰度的关键决定因素，从而揭示了一种机制，通过这种机制，葡萄糖代谢通过组蛋白甲基化影响恶性肿瘤的进展。
Histone lysine methylation functions at the interface of the extracellular environment and intracellular gene expression. DOT1L is a versatile histone H3K79 methyltransferase with a prominent role in MLL-fusion leukemia, yet little is known about how DOT1L responds to extracellular stimuli. Here, we report that DOT1L protein stability is regulated by the extracellular glucose level through the hexosamine biosynthetic pathway (HBP). Mechanistically, DOT1L is O-GlcNAcylated at evolutionarily conserved S1511 in its C terminus. We identify UBE3C as a DOT1L E3 ubiquitin ligase promoting DOT1L degradation whose interaction with DOT1L is susceptible to O-GlcNAcylation. Consequently, HBP enhances H3K79 methylation and expression of critical DOT1L target genes such as HOXA9/MEIS1, promoting cell proliferation in MLL-fusion leukemia. Inhibiting HBP or O-GlcNAc transferase (OGT) increases cellular sensitivity to DOT1L inhibitor. Overall, our work uncovers O-GlcNAcylation and UBE3C as critical determinants of DOT1L protein abundance, revealing a mechanism by which glucose metabolism affects malignancy progression through histone methylation.