Efimova Elena V, Takahashi Satoe, Shamsi Noumaan A, Wu Ding, Labay Edwardine, Ulanovskaya Olesya A, Weichselbaum Ralph R, Kozmin Sergey A, Kron Stephen J
Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois. Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois.
Department of Chemistry, The University of Chicago, Chicago, Illinois.
Mol Cancer Res. 2016 Feb;14(2):173-84. doi: 10.1158/1541-7786.MCR-15-0263. Epub 2015 Nov 4.
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, although 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 (DSB) 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 each 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 nonhomologous end-joining 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.
By defining a pathway from deregulated metabolism to enhanced DNA damage response in cancer, these data provide a rationale for targeting downstream epigenetic effects of metabolic reprogramming to block cancer cell immortality and overcome resistance to genotoxic stress.
传统观点认为癌症中的代谢重编程是为了满足对中间体增加的需求，以支持快速增殖。先前的模型提出这对细胞存活、永生和应激抗性有益，尽管最近对肿瘤代谢物的发现已将注意力转移到影响基因表达的染色质靶点上。为了进一步探索癌症代谢和表观遗传失调的影响，通过追踪照射的MCF7乳腺癌细胞中双链断裂（DSB）的修复情况，研究了用代谢中间体、肿瘤代谢物和/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修复和防止照射后加速衰老中的作用。针对糖酵解和谷氨酰胺分解共有的途径，发现己糖胺生物合成途径（HBP）和三羧酸（TCA）循环具有相反的作用。用HBP代谢物N-乙酰葡糖胺（GlcNAc）处理细胞，或用小分子或靶向O-葡糖胺酶的RNAi增强蛋白质O-糖基化，均可增强DSB修复，而靶向O-葡糖胺转移酶则可逆转GlcNAc的作用。与HBP相反，包括α-酮戊二酸在内的TCA代谢物可阻断DSB的修复。引人注目的是，肿瘤代谢物2-羟基戊二酸（2-HG）可恢复DNA修复。靶向组蛋白甲基化和去甲基化的下游效应器表明PRC1/2多梳复合物是代谢调控的最终靶点，这反映了多梳蛋白家族蛋白在非同源末端连接DSB修复中的已知作用。我们的发现，即癌症代谢重编程的表观遗传效应可能促进DNA修复，提供了一种分子机制，通过这种机制，代谢失调不仅可以支持细胞生长，还可以维持细胞永生、驱动治疗抗性并促进基因组不稳定。
通过定义从癌症中失调的代谢到增强的DNA损伤反应的途径，这些数据为靶向代谢重编程的下游表观遗传效应以阻断癌细胞永生和克服对基因毒性应激的抗性提供了理论依据。
