O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation.
O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation.
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DOI：
10.1038/s41388-022-02237-6
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发表时间：
2022-04
期刊：
影响因子：
8
通讯作者：
Reginato, Mauricio J.
中科院分区：
文献类型：
--
作者：
Ciraku, Lorela;Bacigalupa, Zachary A.;Ju, Jing;Moeller, Rebecca A.;Giang Le Minh;Lee, Rusia H.;Smith, Michael D.;Ferrer, Christina M.;Trefely, Sophie;Izzo, Luke T.;Doan, Mary T.;Gocal, Wiktoria A.;D'Agostino, Luca;Shi, Wenyin;Jackson, Joshua G.;Katsetos, Christos D.;Wellen, Kathryn E.;Snyder, Nathaniel W.;Reginato, Mauricio J.
胶质母细胞瘤（GBM）优先从乙酸产生乙酰辅酶A作为燃料源以促进肿瘤生长。在许多癌症中，O-GlcNAc转移酶（OGT）的增加会导致O-GlcNAc的磷酸化水平升高，而O-GlcNAc磷酸化水平的降低会阻断癌症的生长。在这里，我们确定了一种新的机制，OGT调节醋酸依赖性乙酰辅酶A和脂质的生产，通过调节磷酸化乙酰辅酶A合成酶2（ACSS 2）的细胞周期蛋白依赖性激酶5（CDK 5）。OGT是GBM细胞生长所必需的，并且足以调节乙酸盐转化为乙酰辅酶A和脂质。GBM细胞中O-GlcNAc酰化水平升高会以CDK 5依赖性方式增加Ser-267上ACSS 2的磷酸化。重要的是，我们发现ACSS 2 Ser-267磷酸化通过减少多聚泛素化和降解来调节其稳定性。ACSS 2 Ser-267对于OGT介导的GBM生长至关重要，因为ACSS 2 Ser-267磷酸模拟物的过表达在体外和体内挽救生长。重要的是，我们表明靶向OGT和CDK 5的GBM在体外减少GBM生长。因此，OGT/CDK 5/ACSS 2通路可能是一种靶向脑肿瘤中代谢依赖性改变的方法。
Glioblastomas (GBMs) preferentially generate acetyl-CoA from acetate as a fuel source to promote tumor growth. O-GlcNAcylation has been shown to be elevated by increasing O-GlcNAc transferase (OGT) in many cancers and reduced O-GlcNAcylation can block cancer growth. Here, we identify a novel mechanism whereby OGT regulates acetate-dependent acetyl-CoA and lipid production by regulating phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by cyclin-dependent kinase 5 (CDK5). OGT is required and sufficient for GBM cell growth and regulates acetate conversion to acetyl-CoA and lipids. Elevating O-GlcNAcylation in GBM cells increases phosphorylation of ACSS2 on Ser-267 in a CDK5-dependent manner. Importantly, we show that ACSS2 Ser-267 phosphorylation regulates its stability by reducing polyubiquitination and degradation. ACSS2 Ser-267 is critical for OGT-mediated GBM growth as overexpression of ACSS2 Ser-267 phospho-mimetic rescues growth in vitro and in vivo. Importantly, we show that pharmacologically targeting OGT and CDK5 reduces GBM growth ex vivo. Thus, the OGT/CDK5/ACSS2 pathway may be a way to target altered metabolic dependencies in brain tumors.
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影响因子：
4.8
作者：
Lin, Ho;Chen, Mei-Chih;Lin, Shih-Yi
通讯作者：
Lin, Shih-Yi
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
细胞周期蛋白依赖性激酶抑制剂 dinaciclib 在卵巢癌临床前模型中与顺铂具有有效协同作用
影响因子：
--
作者：
Chen XX;Xie FF;Zhu XJ;Lin F;Pan SS;Gong LH;Qiu JG;Zhang WJ;Jiang QW;Mei XL;Xue YQ;Qin WM;Shi Z;Yan XJ
通讯作者：
Yan XJ
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：
14.9
作者：
Hornbeck PV;Zhang B;Murray B;Kornhauser JM;Latham V;Skrzypek E
通讯作者：
Skrzypek E