Wilde Blake R, Ayer Donald E
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112-5550, USA.
Br J Cancer. 2015 Dec 1;113(11):1529-33. doi: 10.1038/bjc.2015.360. Epub 2015 Oct 15.
Metabolic reprogramming towards aerobic glycolysis is a common feature of transformed cells and can be driven by a network of transcription factors. It is well established that c-Myc and hypoxia-inducible factor-1α (HIF-1α) contribute to metabolic reprogramming by driving the expression of glycolytic target genes. More recently, the c-Myc-related transcription factor MondoA has been shown to restrict glucose uptake and aerobic glycolysis via its induction of thioredoxin-interacting protein (TXNIP). Three recent studies demonstrate that complex and cancer type-specific interactions between c-Myc, MondoA and HIF-1α underlie metabolism, tumourigenesis and drug response. In triple-negative breast cancer, c-Myc blocks MondoA-dependent activation of TXNIP to stimulate aerobic glycolysis. In contrast, in neuroblastoma, N-Myc requires MondoA for metabolic reprogramming and tumourigenesis. Finally, the therapeutic response of BRAF(V600E) melanoma cells to vemurafenib requires downregulation of c-Myc and HIF-1α and upregulation of MondoA-TXNIP, and the subsequent reprogramming away from aerobic glycolysis. In this minireview we highlight the findings in these three studies and present a working model to explain why c-Myc and MondoA function cooperatively in some cancers and antagonistically in others.
向有氧糖酵解的代谢重编程是转化细胞的一个共同特征，并且可以由一个转录因子网络驱动。众所周知，c-Myc和缺氧诱导因子-1α（HIF-1α）通过驱动糖酵解靶基因的表达来促进代谢重编程。最近，与c-Myc相关的转录因子MondoA已被证明通过诱导硫氧还蛋白相互作用蛋白（TXNIP）来限制葡萄糖摄取和有氧糖酵解。最近的三项研究表明，c-Myc、MondoA和HIF-1α之间复杂且癌症类型特异性的相互作用是代谢、肿瘤发生和药物反应的基础。在三阴性乳腺癌中，c-Myc阻断MondoA依赖的TXNIP激活以刺激有氧糖酵解。相反，在神经母细胞瘤中，N-Myc需要MondoA进行代谢重编程和肿瘤发生。最后，BRAF（V600E）黑色素瘤细胞对维莫非尼的治疗反应需要下调c-Myc和HIF-1α并上调MondoA-TXNIP，以及随后从有氧糖酵解进行重编程。在这篇综述中，我们强调了这三项研究中的发现，并提出了一个工作模型来解释为什么c-Myc和MondoA在某些癌症中协同发挥作用，而在其他癌症中则相互拮抗。
