R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m(6)A/MYC/CEBPA Signaling.
R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m(6)A/MYC/CEBPA Signaling.
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R-2HG 通过靶向 FTO/m(6)A/MYC/CEBPA 信号发挥抗肿瘤活性
DOI：
10.1016/j.cell.2017.11.031
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发表时间：
2018-01-11
期刊：
影响因子：
64.5
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Su R;Dong L;Li C;Nachtergaele S;Wunderlich M;Qing Y;Deng X;Wang Y;Weng X;Hu C;Yu M;Skibbe J;Dai Q;Zou D;Wu T;Yu K;Weng H;Huang H;Ferchen K;Qin X;Zhang B;Qi J;Sasaki AT;Plas DR;Bradner JE;Wei M;Marcucci G;Jiang X;Mulloy JC;Jin J;He C;Chen J
R-2-羟基戊二酸（R-2 HG）是由突变型异柠檬酸脱氢酶1/2（IDH 1/2）酶高水平产生的一种致癌代谢物。我们在这里表明，R-2 HG也发挥了广泛的抗白血病活性在体外和体内抑制白血病细胞增殖/活力，促进细胞周期阻滞和凋亡。从机制上讲，R-2 HG抑制FTO活性，从而增加R-2 HG敏感性白血病细胞中的整体N6-甲基腺苷（m6 A）RNA修饰，这反过来又降低了MYC/CEBPA转录物的稳定性，导致相关途径的抑制。异位表达的突变体IDH 1和S-2 HG重现了R-2 HG的作用。高水平的FTO使白血病细胞对R-2 HG敏感，而MYC信号传导的过度活化赋予可通过抑制MYC信号传导逆转的抗性。R-2 HG在神经胶质瘤中也显示出抗肿瘤活性。总的来说，虽然在IDH 1/2突变型癌症中积累的R-2 HG有助于癌症起始，但我们的工作证明了2 HG通过靶向FTO/m6 A/MYC/CEBPA信号传导抑制FTO高癌细胞的增殖/存活的抗肿瘤作用。虽然癌代谢物R-2-羟基戊二酸（R-2 HG）的积累有助于癌症的发生，但它也通过增加整体N6-甲基腺苷（m6 A）RNA修饰而具有抗肿瘤作用。
R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability, and promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits FTO activity, thereby increasing global N6-methyladenosine (m6A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways. Ectopically expressed mutant IDH1 and S-2HG recapitulate the effects of R-2HG. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. Collectively, while R-2HG accumulated in IDH1/2-mutant cancers contributes to cancer initiation, our work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m6A/MYC/CEBPA signaling. While accumulation of the oncometabolite R-2-hydroxyglutarate (R-2HG) contributes to cancer initiation, it also has anti-tumor effects by increasing global N6-methyladenosine (m6A) RNA modification.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
DOI：
10.1056/nejmoa1407279
发表时间：
2015-06-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Eckel-Passow JE;Lachance DH;Molinaro AM;Walsh KM;Decker PA;Sicotte H;Pekmezci M;Rice T;Kosel ML;Smirnov IV;Sarkar G;Caron AA;Kollmeyer TM;Praska CE;Chada AR;Halder C;Hansen HM;McCoy LS;Bracci PM;Marshall R;Zheng S;Reis GF;Pico AR;O'Neill BP;Buckner JC;Giannini C;Huse JT;Perry A;Tihan T;Berger MS;Chang SM;Prados MD;Wiemels J;Wiencke JK;Wrensch MR;Jenkins RB
通讯作者：
Jenkins RB
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
50.3
作者：
Li Z;Weng H;Su R;Weng X;Zuo Z;Li C;Huang H;Nachtergaele S;Dong L;Hu C;Qin X;Tang L;Wang Y;Hong GM;Huang H;Wang X;Chen P;Gurbuxani S;Arnovitz S;Li Y;Li S;Strong J;Neilly MB;Larson RA;Jiang X;Zhang P;Jin J;He C;Chen J
通讯作者：
Chen J