UCSF

Reprogramming of Glutamate Metabolism and Redox Homeostasis in De Novo MYC-Driven Liver Tumors

Brittany Anderton

MYC overexpressing cells frequently exhibit increased dependence on uptake of glutamine and its conversion to glutamate. However, whether MYC shapes downstream glutamate utilization decisions in vivo is poorly understood. We employed integrated gene expression and metabolite profiling analyses to identify novel metabolic pathways that are altered in primary MYC-driven liver cancers. We identified six metabolic pathways deregulated in MYC-driven liver tumors, including glutathione metabolism. In primary, MYC-driven tumors, glutamine-derived carbons preferentially enter central carbon metabolism and proliferative metabolic pathways and have diminished incorporation into glutathione and its precursor metabolite. We find that protein expression of the rate-limiting enzyme of glutathione synthesis, GCLC, is suppressed in a MYC-dependent manner. We further show that GCLC is targeted by a MYC-induced microRNA, miR-18a. MiR-18a expression is elevated in human hepatocellular carcinoma (HCC) and correlates with altered glutathione pathway gene expression. Further, poorly differentiated human HCCs have low tumor glutathione levels. MYC-driven liver tumors compensate for loss of glutathione by upregulating several antioxidant regeneration pathways. However, MYC-driven liver tumors exhibit increased sensitivity to exogenous oxidative stress, as demonstrated by tumor-specific fat accumulation and cell death following treatment with the potent oxidant diquat. Thus, despite sufficient antioxidant capacity at baseline, MYC-driven liver tumors are sensitive to exogenous oxidative stress. In total, we show that MYC regulates glutamate utilization by attenuating glutathione production via miR-18a, leading to preferential shunting of glutamate toward proliferative metabolism in tumors and altering redox homeostasis mechanisms.