O-GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway.
O-GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway.
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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还没有很好地理解。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。癌症显示出升高的O-GlcNAc化，并且抑制O-GlcNAc化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SIRT 1。减少O-GlcNAc酰化以AMPK依赖性方式提高SIRT 1水平和活性。癌细胞中O-GlcNAc化的减少导致SIRT 1介导的致癌转录因子FOXM 1以MEK/ERK依赖性方式的蛋白酶体降解。SIRT 1对OGT介导的FOXM 1泛素化调节至关重要，降低SIRT 1活性可逆转OGT介导的FOXM 1调节。此外，我们发现SIRT 1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-GlcNAc化是通过SIRT 1/ /FOXM 1轴将代谢与侵袭和转移联系起来的中心组分。
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-dependent manner. Reduced O-GlcNAcylation in cancer cells leads to SIRT1-mediated proteasomal degradation of oncogenic transcription factor FOXM1 in a 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 a SIRT1/ /FOXM1 axis.
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DOI：
10.1126/science.1231097
发表时间：
2013-03-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hubbard BP;Gomes AP;Dai H;Li J;Case AW;Considine T;Riera TV;Lee JE;E SY;Lamming DW;Pentelute BL;Schuman ER;Stevens LA;Ling AJ;Armour SM;Michan S;Zhao H;Jiang Y;Sweitzer SM;Blum CA;Disch JS;Ng PY;Howitz KT;Rolo AP;Hamuro Y;Moss J;Perni RB;Ellis JL;Vlasuk GP;Sinclair DA
通讯作者：
Sinclair DA
DOI：
10.1083/jcb.201501101
发表时间：
2015-03-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bond MR;Hanover JA
通讯作者：
Hanover JA
DOI：
10.1146/annurev.pathol.4.110807.092250
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Haigis MC;Sinclair DA
通讯作者：
Sinclair DA
影响因子：
16
作者：
Ferrer, Christina M.;Lynch, Thomas P.;Sodi, Valerie L.;Falcone, John N.;Schwab, Luciana P.;Peacock, Danielle L.;Vocadlo, David J.;Seagroves, Tiffany N.;Reginato, Mauricio J.
通讯作者：
Reginato, Mauricio J.
影响因子：
4
作者：
Choi, Jee-Eun;Mostoslavsky, Raul
通讯作者：
Mostoslavsky, Raul