R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling.,Cell

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R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling.
Cell ( IF 45.5 ) Pub Date : 2018-01-11 , DOI: 10.1016/j.cell.2017.11.031
Rui Su ₁ , Lei Dong ₁ , Chenying Li ₂ , Sigrid Nachtergaele ₃ , Mark Wunderlich ₄ , Ying Qing ₁ , Xiaolan Deng ₅ , Yungui Wang ₂ , Xiaocheng Weng ₆ , Chao Hu ₂ , Mengxia Yu ₇ , Jennifer Skibbe ₁ , Qing Dai ₃ , Dongling Zou ₈ , Tong Wu ₃ , Kangkang Yu ₃ , Hengyou Weng ₁ , Huilin Huang ₁ , Kyle Ferchen ₁ , Xi Qin ₁ , Bin Zhang ₉ , Jun Qi ₁₀ , Atsuo T Sasaki ₁₁ , David R Plas ₁ , James E Bradner ₁₀ , Minjie Wei ₁₂ , Guido Marcucci ₉ , Xi Jiang ₁ , James C Mulloy ₄ , Jie Jin ₇ , Chuan He ₃ , Jianjun Chen ₁₃

Affiliation

Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA.
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; Key Laboratory of Hematopoietic Malignancies, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China.
Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China.
Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA; College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, Wuhan University, Hubei, Wuhan 430072, China.
Key Laboratory of Hematopoietic Malignancies, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China.
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; Depart of Gynecologic Oncology, Chongqing Cancer Institute and Hospital and Cancer Center, Chongqing 400030, China.
Gehr Family Center for Leukemia Research, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China.
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; Gehr Family Center for Leukemia Research, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA.

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 by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (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.

中文翻译：

R-2HG 通过靶向 FTO/m6A/MYC/CEBPA 信号显示抗肿瘤活性。

据报道，由突变异柠檬酸脱氢酶 1/2 (IDH1/2) 酶高水平产生的 R-2-羟基戊二酸 (R-2HG) 是一种致癌代谢物。我们在这里表明，R-2HG 通过抑制白血病细胞增殖/活力和促进细胞周期停滞和细胞凋亡，在体外和体内也发挥广泛的抗白血病活性。从机制上讲，R-2HG 抑制脂肪量和肥胖相关蛋白 (FTO) 活性，从而增加整体 N ⁶ -甲基腺苷 (m ⁶A) R-2HG 敏感性白血病细胞中的 RNA 修饰，进而降低 MYC/CEBPA 转录物的稳定性，导致相关通路的抑制。异位表达的突变体 IDH1 和 S-2HG 概括了 R-2HG 的作用。高水平的 FTO 使白血病细胞对 R-2HG 敏感，而 MYC 信号传导的过度激活赋予抗性，可以通过抑制 MYC 信号传导来逆转。R-2HG 在胶质瘤中也显示出抗肿瘤活性。^{总的来说，虽然 R-2HG 在 IDH1/2 突变癌症中积累有助于癌症的发生，但我们的工作证明了 2HG 通过靶向 FTO/m 6} A/MYC/CEBPA 信号传导抑制 FTO 高癌细胞增殖/存活的抗肿瘤作用.

更新日期：2017-12-15

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