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营养传感器 O-GlcNAc 转移酶通过 SREBP-1 调控控制癌症脂质代谢。

Nutrient sensor O-GlcNAc transferase controls cancer lipid metabolism via SREBP-1 regulation.

机构信息

Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.

Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

出版信息

Oncogene. 2018 Feb 15;37(7):924-934. doi: 10.1038/onc.2017.395. Epub 2017 Oct 23.

DOI:10.1038/onc.2017.395
PMID:29059153
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5814337/
Abstract

Elevated O-GlcNAcylation is associated with disease states such as diabetes and cancer. O-GlcNAc transferase (OGT) is elevated in multiple cancers and inhibition of this enzyme genetically or pharmacologically inhibits oncogenesis. Here we show that O-GlcNAcylation modulates lipid metabolism in cancer cells. OGT regulates expression of the master lipid regulator the transcription factor sterol regulatory element binding protein 1 (SREBP-1) and its transcriptional targets both in cancer and lipogenic tissue. OGT regulates SREBP-1 protein expression via AMP-activated protein kinase (AMPK). SREBP-1 is critical for OGT-mediated regulation of cell survival and of lipid synthesis, as overexpression of SREBP-1 rescues lipogenic defects associated with OGT suppression, and tumor growth in vitro and in vivo. These results unravel a previously unidentified link between O-GlcNAcylation, lipid metabolism and the regulation of SREBP-1 in cancer and suggests a crucial role for O-GlcNAc signaling in transducing nutritional state to regulate lipid metabolism.

摘要

糖基化（O-GlcNAcylation）水平升高与糖尿病和癌症等疾病状态有关。在多种癌症中，O-连接的 N-乙酰葡萄糖胺转移酶（OGT）的水平升高，而该酶的遗传或药理学抑制可抑制肿瘤发生。在这里，我们表明糖基化修饰可调节癌细胞中的脂质代谢。OGT 调节脂质调节因子固醇调节元件结合蛋白 1（SREBP-1）及其在癌症和生脂组织中的转录靶标的表达。OGT 通过 AMP 激活的蛋白激酶（AMPK）调节 SREBP-1 蛋白的表达。SREBP-1 对于 OGT 介导的细胞存活和脂质合成的调节至关重要，因为 SREBP-1 的过表达可挽救与 OGT 抑制相关的生脂缺陷，并可挽救体外和体内的肿瘤生长。这些结果揭示了糖基化、脂质代谢和 SREBP-1 在癌症中的调控之间以前未被识别的联系，并表明 O-GlcNAc 信号在将营养状态转导为调节脂质代谢方面起着关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56af/5814337/d9b3f55e3478/nihms904396f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56af/5814337/bb05e72de6b2/nihms904396f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56af/5814337/81ef793a943c/nihms904396f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56af/5814337/2ef4a7927999/nihms904396f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56af/5814337/11071639723d/nihms904396f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56af/5814337/d9b3f55e3478/nihms904396f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56af/5814337/bb05e72de6b2/nihms904396f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56af/5814337/6a286e517490/nihms904396f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56af/5814337/7cf42a64e7ba/nihms904396f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56af/5814337/81ef793a943c/nihms904396f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56af/5814337/2ef4a7927999/nihms904396f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56af/5814337/11071639723d/nihms904396f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56af/5814337/d9b3f55e3478/nihms904396f7.jpg

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