Sodi Valerie L, Khaku Sakina, Krutilina Raisa, Schwab Luciana P, Vocadlo David J, Seagroves Tiffany N, Reginato Mauricio J
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
Center for Adult Cancer Research and the Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee.
Mol Cancer Res. 2015 May;13(5):923-33. doi: 10.1158/1541-7786.MCR-14-0536. Epub 2015 Jan 30.
Cancers exhibit altered metabolism characterized by increased glucose and glutamine uptake. The hexosamine biosynthetic pathway (HBP) uses glucose and glutamine, and directly contributes to O-linked-β-N-acetylglucosamine (O-GlcNAc) modifications on intracellular proteins. Multiple tumor types contain elevated total O-GlcNAcylation, in part, by increasing O-GlcNAc transferase (OGT) levels, the enzyme that catalyzes this modification. Although cancer cells require OGT for oncogenesis, it is not clear how tumor cells regulate OGT expression and O-GlcNAcylation. Here, it is shown that the PI3K-mTOR-MYC signaling pathway is required for elevation of OGT and O-GlcNAcylation in breast cancer cells. Treatment with PI3K and mTOR inhibitors reduced OGT protein expression and decreased levels of overall O-GlcNAcylation. In addition, both AKT and mTOR activation is sufficient to elevate OGT/O-GlcNAcylation. Downstream of mTOR, the oncogenic transcription factor c-MYC is required and sufficient for increased OGT protein expression in an RNA-independent manner and c-MYC regulation of OGT mechanistically requires the expression of c-MYC transcriptional target HSP90A. Finally, mammary tumor epithelial cells derived from MMTV-c-myc transgenic mice contain elevated OGT and O-GlcNAcylation and OGT inhibition in this model induces apoptosis. Thus, OGT and O-GlcNAcylation levels are elevated via activation of an mTOR/MYC cascade.
Evidence indicates OGT as a therapeutic target in c-MYC-amplified cancers.
癌症表现出代谢改变，其特征是葡萄糖和谷氨酰胺摄取增加。己糖胺生物合成途径（HBP）利用葡萄糖和谷氨酰胺，并直接促进细胞内蛋白质的O-连接β-N-乙酰葡糖胺（O-GlcNAc）修饰。多种肿瘤类型的总O-GlcNAcylation水平升高，部分原因是增加了催化这种修饰的O-GlcNAc转移酶（OGT）水平。虽然癌细胞的肿瘤发生需要OGT，但尚不清楚肿瘤细胞如何调节OGT表达和O-GlcNAcylation。在这里，研究表明PI3K-mTOR-MYC信号通路是乳腺癌细胞中OGT和O-GlcNAcylation升高所必需的。用PI3K和mTOR抑制剂处理可降低OGT蛋白表达并降低总体O-GlcNAcylation水平。此外，AKT和mTOR的激活都足以提高OGT/O-GlcNAcylation。在mTOR的下游，致癌转录因子c-MYC是以RNA非依赖方式增加OGT蛋白表达所必需且足够的，并且c-MYC对OGT的调节机制上需要c-MYC转录靶标HSP90A的表达。最后，源自MMTV-c-myc转基因小鼠的乳腺肿瘤上皮细胞含有升高的OGT和O-GlcNAcylation，并且在该模型中OGT抑制诱导细胞凋亡。因此，OGT和O-GlcNAcylation水平通过mTOR/MYC级联的激活而升高。
有证据表明OGT是c-MYC扩增癌症中的治疗靶点。
