生物
转移
癌症研究
MAPK/ERK通路
福克斯M1
转录因子
安普克
癌细胞
细胞生物学
NAD+激酶
癌症
蛋白激酶A
激酶
生物化学
酶
遗传学
基因
作者
Christina M. Ferrer,Tong Y. Lu,Zachary A. Bacigalupa,Christos D. Katsetos,David A. Sinclair,Mauricio J. Reginato
出处
期刊:Oncogene
[Springer Nature]
日期:2016-06-27
卷期号:36 (4): 559-569
被引量:79
摘要
Tumors utilize aerobic glycolysis to support growth and invasion. However, the molecular mechanisms that link metabolism with invasion are not well understood. The nutrient sensor O-linked-β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) modifies intracellular proteins with N-acetylglucosamine. Cancers display elevated O-GlcNAcylation and suppression of O-GlcNAcylation inhibits cancer invasion and metastasis. Here, we show that the regulation of cancer invasion by OGT is dependent on the NAD+-dependent deacetylase SIRT1. Reducing O-GlcNAcylation elevates SIRT1 levels and activity in an AMPK (AMP-activated protein kinase α)-dependent manner. Reduced O-GlcNAcylation in cancer cells leads to SIRT1-mediated proteasomal degradation of oncogenic transcription factor FOXM1 in an MEK/ERK-dependent manner. SIRT1 is critical for OGT-mediated regulation of FOXM1 ubiquitination and reducing SIRT1 activity reverses OGT-mediated regulation of FOXM1. Moreover, we show that SIRT1 levels are required for OGT-mediated regulation of invasion and metastasis in breast cancer cells. Thus, O-GlcNAcylation is a central component linking metabolism to invasion and metastasis via an SIRT1/ERK/FOXM1 axis.
科研通智能强力驱动
Strongly Powered by AbleSci AI