Anderton Brittany, Camarda Roman, Balakrishnan Sanjeev, Balakrishnan Asha, Kohnz Rebecca A, Lim Lionel, Evason Kimberley J, Momcilovic Olga, Kruttwig Klaus, Huang Qiang, Xu Guowang, Nomura Daniel K, Goga Andrei
Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
EMBO Rep. 2017 Apr;18(4):569-585. doi: 10.15252/embr.201643068. Epub 2017 Feb 20.
How MYC reprograms metabolism in primary tumors remains poorly understood. Using integrated gene expression and metabolite profiling, we identify six pathways that are coordinately deregulated in primary MYC-driven liver tumors: glutathione metabolism; glycine, serine, and threonine metabolism; aminoacyl-tRNA biosynthesis; cysteine and methionine metabolism; ABC transporters; and mineral absorption. We then focus our attention on glutathione (GSH) and glutathione disulfide (GSSG), as they are markedly decreased in MYC-driven tumors. We find that fewer glutamine-derived carbons are incorporated into GSH in tumor tissue relative to non-tumor tissue. Expression of GCLC, the rate-limiting enzyme of GSH synthesis, is attenuated by the MYC-induced microRNA miR-18a. Inhibition of miR-18a leads to increased GCLC protein expression and GSH abundance in tumor tissue. Finally, MYC-driven liver tumors exhibit increased sensitivity to acute oxidative stress. In summary, MYC-dependent attenuation of GCLC by miR-18a contributes to GSH depletion , and low GSH corresponds with increased sensitivity to oxidative stress in tumors. Our results identify new metabolic pathways deregulated in primary MYC tumors and implicate a role for MYC in regulating a major antioxidant pathway downstream of glutamine.
MYC如何在原发性肿瘤中重编程代谢仍知之甚少。通过整合基因表达和代谢物谱分析，我们确定了在原发性MYC驱动的肝肿瘤中协同失调的六条途径：谷胱甘肽代谢；甘氨酸、丝氨酸和苏氨酸代谢；氨酰-tRNA生物合成；半胱氨酸和甲硫氨酸代谢；ABC转运蛋白；以及矿物质吸收。然后，我们将注意力集中在谷胱甘肽（GSH）和谷胱甘肽二硫化物（GSSG）上，因为它们在MYC驱动的肿瘤中显著减少。我们发现，相对于非肿瘤组织，肿瘤组织中较少的谷氨酰胺衍生碳被整合到GSH中。GSH合成的限速酶GCLC的表达被MYC诱导的微小RNA miR-18a减弱。抑制miR-18a会导致肿瘤组织中GCLC蛋白表达和GSH丰度增加。最后，MYC驱动的肝肿瘤对急性氧化应激表现出更高的敏感性。总之，miR-18a对GCLC的MYC依赖性减弱导致GSH耗竭，而低GSH与肿瘤对氧化应激的敏感性增加相对应。我们的结果确定了原发性MYC肿瘤中失调的新代谢途径，并暗示了MYC在调节谷氨酰胺下游主要抗氧化途径中的作用。
