Linking Cancer Metabolism to DNA Repair and Accelerated Senescence.
Linking Cancer Metabolism to DNA Repair and Accelerated Senescence.
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DOI：
10.1158/1541-7786.mcr-15-0263
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
Kron SJ
中科院分区：
文献类型：
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作者：
Efimova EV;Takahashi S;Shamsi NA;Wu D;Labay E;Ulanovskaya OA;Weichselbaum RR;Kozmin SA;Kron SJ
传统观点将癌症中的代谢重编程归因于满足对支持快速增殖的中间体不断增加的需求。先前的模型已经提出了对细胞存活、永生和抗应激的益处，而最近发现的致癌代谢物已将注意力转移到影响基因表达的染色质靶标上。为了进一步探索癌症代谢和表观遗传失调的影响，通过跟踪受辐射的 MCF7 乳腺癌细胞中双链断裂 (DSB) 的解析，检查了用代谢中间体、致癌代谢物和/或代谢抑制剂处理的细胞中的 DNA 修复动力学。破坏癌症代谢揭示了糖酵解和谷氨酰胺分解在促进 DSB 修复和防止辐射后加速衰老方面的作用。糖酵解和谷氨酰胺分解常见的靶向途径揭示了己糖胺生物合成途径（HBP）和三羧酸（TCA）循环的相反作用。用 HBP 代谢物 N-乙酰氨基葡萄糖 (GlcNAc) 处理细胞或用小分子增强蛋白 O-GlcNAc 酰化或靶向 O-GlcNAcase 的 RNAi 增强 DSB 修复，同时靶向 O-GlcNAc 转移酶可逆转 GlcNAc 的作用。与 HBP 相反，TCA 代谢物（包括 α-酮戊二酸）阻碍 DSB 解析。引人注目的是，致癌代谢物 2-羟基戊二酸 (2-HG) 可以恢复 DNA 修复。以组蛋白甲基化和去甲基化的下游效应子为目标，表明 PRC1/2 Polycomb 复合物是代谢调节的最终目标，反映了 Polycomb 组蛋白在非同源末端连接 (NHEJ) DSB 修复中的已知作用。我们的研究结果表明，癌症代谢重编程的表观遗传效应可能会促进 DNA 修复，这提供了一种分子机制，通过该机制，代谢失调不仅可以支持细胞生长，还可以维持细胞永生，驱动治疗耐药性并促进基因组不稳定。
Conventional wisdom ascribes metabolic reprogramming in cancer to meeting increased demands for intermediates to support rapid proliferation. Prior models have proposed benefits toward cell survival, immortality and stress resistance while the recent discovery of oncometabolites has shifted attention to chromatin targets affecting gene expression. To explore further effects of cancer metabolism and epigenetic deregulation, DNA repair kinetics were examined in cells treated with metabolic intermediates, oncometabolites and/or metabolic inhibitors by tracking resolution of double strand breaks (DSBs) in irradiated MCF7 breast cancer cells. Disrupting cancer metabolism revealed roles for both glycolysis and glutaminolysis in promoting DSB repair and preventing accelerated senescence after irradiation. Targeting pathways common to glycolysis and glutaminolysis uncovered opposing effects of the hexosamine biosynthetic pathway (HBP) and tricarboxylic acid (TCA) cycle. Treating cells with the HBP metabolite N-acetylglucosamine (GlcNAc) or augmenting protein O-GlcNAcylation with small molecules or RNAi targeting O-GlcNAcase enhanced DSB repair, while targeting O-GlcNAc transferase reversed GlcNAc’s effects. Opposing the HBP, TCA metabolites including α-ketoglutarate blocked DSB resolution. Strikingly, DNA repair could be restored by the oncometabolite 2-hydroxyglutarate (2-HG). Targeting downstream effectors of histone methylation and demethylation implicated the PRC1/2 polycomb complexes as the ultimate targets for metabolic regulation, reflecting known roles for Polycomb group proteins in non-homologous end-joining (NHEJ) DSB repair. Our findings that epigenetic effects of cancer metabolic reprogramming may promote DNA repair provide a molecular mechanism by which deregulation of metabolism may not only support cell growth but also maintain cell immortality, drive therapeutic resistance and promote genomic instability.