NEAT1 is essential for metabolic changes that promote breast cancer growth and metastasis.
NEAT1 is essential for metabolic changes that promote breast cancer growth and metastasis.
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DOI：
10.1016/j.cmet.2021.11.011
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发表时间：
2021-12-07
期刊：
影响因子：
29
通讯作者：
Song MS
中科院分区：
文献类型：
--
作者：
Park MK;Zhang L;Min KW;Cho JH;Yeh CC;Moon H;Hormaechea-Agulla D;Mun H;Ko S;Lee JW;Jathar S;Smith AS;Yao Y;Giang NT;Vu HH;Yan VC;Bridges MC;Kourtidis A;Muller F;Chang JH;Song SJ;Nakagawa S;Hirose T;Yoon JH;Song MS
糖酵解加速是癌症中观察到的主要代谢变化，但其潜在的分子机制及其在癌症进展中的作用仍然知之甚少。在这里，我们表明，在MMTV-PyVT小鼠中，长非编码RNA(LncRNA)Neat1的缺失严重损害了肿瘤的启动、生长和转移，同时特异性地切断了糖酵解的倒数第二步。在力学上，NEAT1直接结合并形成组装PGK1/PGAM1/ENO1复合体的支架桥，从而促进底物通道，实现高效的糖酵解。值得注意的是，NEAT1在癌症患者中上调，并与这些复合体的高水平相关，基因和药物阻断倒数第二糖酵解可以消除NEAT1依赖的肿瘤形成。最后，我们证明了Pinin介导了葡萄糖刺激的NEAT1的核输出，通过它发挥了异构体特异性和类斑点非依赖的功能。这些发现确立了NEAT1在调节肿瘤新陈代谢中的直接作用，提供了对Warburg效应的新见解，并确定了潜在的治疗靶点。Park等人。关于NEAT1在促进乳腺癌糖酵解状态中的作用的报告，强调了lncRNAs如何在体内代谢水平上调节癌症的发展。NEAT1促进PGK1/PGAM1/ENO1糖酵解复合体的组装和底物通道。通过异构体转换，他们确定了NEAT1在肿瘤发生中的异构体特异性、类斑点无关的作用。
Accelerated glycolysis is the main metabolic change observed in cancer, but the underlying molecular mechanisms and their role in cancer progression remain poorly understood. Here we show that deletion of the long noncoding RNA (lncRNA) Neat1 in MMTV-PyVT mice profoundly impairs tumor initiation, growth and metastasis, while specifically switching off the penultimate step of glycolysis. Mechanistically, NEAT1 directly binds and forms a scaffold bridge for the assembly of PGK1/PGAM1/ENO1 complexes, and thereby promotes substrate channeling for high and efficient glycolysis. Notably, NEAT1 is upregulated in cancer patients and correlates with high levels of these complexes, and genetic and pharmacological blockade of penultimate glycolysis ablates NEAT1-dependent tumorigenesis. Finally, we demonstrate that Pinin mediates glucose-stimulated nuclear export of NEAT1, through which it exerts isoform-specific and paraspeckle-independent functions. These findings establish a direct role for NEAT1 in regulating tumor metabolism, provide new insights into the Warburg effect, and identify potential targets for therapy. Park et al. report on a role for NEAT1 in promoting a glycolytic state in breast cancer, highlighting how lncRNAs regulate cancer development at a metabolic level in vivo. NEAT1 facilitates assembly of PGK1/PGAM1/ENO1 glycolytic complexes and substrate channeling. Through isoform switching, they identify an isoform-specific, paraspeckle-independent role for NEAT1 in tumorigenesis.
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影响因子：
64.8
作者：
Konermann S;Brigham MD;Trevino AE;Joung J;Abudayyeh OO;Barcena C;Hsu PD;Habib N;Gootenberg JS;Nishimasu H;Nureki O;Zhang F
通讯作者：
Zhang F
影响因子：
5.3
作者：
Alpatov, R;Munguba, GC;Sugrue, SP
通讯作者：
Sugrue, SP
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
46.9
作者：
Castellana M;Wilson MZ;Xu Y;Joshi P;Cristea IM;Rabinowitz JD;Gitai Z;Wingreen NS
通讯作者：
Wingreen NS
影响因子：
29
作者：
Liberti MV;Dai Z;Wardell SE;Baccile JA;Liu X;Gao X;Baldi R;Mehrmohamadi M;Johnson MO;Madhukar NS;Shestov AA;Chio IIC;Elemento O;Rathmell JC;Schroeder FC;McDonnell DP;Locasale JW
通讯作者：
Locasale JW