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 in vivo 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 in vivo, 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.
This study shows that MYC inhibits GCLC, the rate‐limiting enzyme of glutathione synthesis, via the microRNA miR‐18a in primary tumors. Therefore, MYC‐driven liver tumors with low total tissue levels of glutathione exhibit increased sensitivity to a potent oxidant.
Six metabolic pathways deregulated by MYC in primary liver tumors are identified using integrated biochemical and gene expression analyses.
Total glutathione (GSH) levels are depleted in MYC‐driven liver tumors, which is associated with reduced glutathione synthesis.
GCLC, the rate‐limiting enzyme of GSH synthesis, is attenuated by the MYC‐induced miR‐18a.
Exogenous treatment of primary MYC liver tumors with the oxidant diquat specifically induces tumor cell death and diminishes MYC expression in surviving tumor cells.
- Received July 15, 2016.
- Revision received January 8, 2017.
- Accepted January 13, 2017.
- © 2017 The Authors
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