Ferrer C M, Lu T Y, Bacigalupa Z A, Katsetos C D, Sinclair D A, Reginato M J
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, PA, USA.
Oncogene. 2017 Jan 26;36(4):559-569. doi: 10.1038/onc.2016.228. Epub 2016 Jun 27.
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.
肿瘤利用有氧糖酵解来支持生长和侵袭。然而，将代谢与侵袭联系起来的分子机制尚未完全了解。营养传感器O-连接-β-N-乙酰葡糖胺（O-GlcNAc）转移酶（OGT）用N-乙酰葡糖胺修饰细胞内蛋白质。癌症表现出O-GlcNAcylation升高，而抑制O-GlcNAcylation可抑制癌症侵袭和转移。在这里，我们表明OGT对癌症侵袭的调节依赖于NAD依赖性脱乙酰酶SIRT1。降低O-GlcNAcylation以AMPK（AMP激活的蛋白激酶α）依赖性方式提高SIRT1水平和活性。癌细胞中O-GlcNAcylation的降低导致SIRT1介导的致癌转录因子FOXM1以MEK/ERK依赖性方式被蛋白酶体降解。SIRT1对于OGT介导的FOXM1泛素化调节至关重要，降低SIRT1活性可逆转OGT介导的FOXM1调节。此外，我们表明SIRT1水平是OGT介导的乳腺癌细胞侵袭和转移调节所必需的。因此，O-GlcNAcylation是通过SIRT1/ERK/FOXM1轴将代谢与侵袭和转移联系起来的核心组成部分。
