MONDOA Is Required for MYC-Driven Metabolic Changes

Upregulation of MYC proteins in cancer cells alters transcription of genes that enact the widespread metabolic changes necessary to support biosynthesis for increased growth and proliferation. MYC proteins are part of a larger network of basic-helix-loop-helix–leucine zipper proteins that regulate gene expression in response to various environmental cues, but it is not clear how or whether components of this extended network contribute to MYC-driven tumorigenesis. Carroll, Diolaiti, and colleagues performed an RNAi screen of MYC network genes and found that MONDOA (also known as MLX-interacting protein, or MLXIP) knockdown was selectively lethal to fibroblasts and cancer cell lines overexpressing MYC or MYCN. In MYCN-overexpressing cells, MONDOA loss attenuated changes in expression of MYCN target genes, particularly those involved in metabolism. Many of these metabolic pathway genes were required for the survival of MYCN-overexpressing neuroblastoma cells, suggesting that the synthetic lethality between MONDOA loss and MYC overexpression was due to disruption of MYC-driven metabolic reprogramming. Metabolomic profiling of MYCN-overexpressing cells indicated that MONDOA knockdown reduced glutamine uptake in association with a reduction in both glutamine-derived tricarboxylic acid cycle intermediates and glutamine-derived lipid biosynthetic pathway intermediates. MYCN-overexpressing cells were also hypersensitive to inhibitors of lipid biosynthesis, underscoring the significant role of lipogenesis in the metabolic reprogramming that supports the growth and proliferation of MYC-driven cancers. High expression of MYC and MONDOA metabolic pathway target genes was associated with shorter overall survival in several cancer types, further pointing to cooperation between MYC and MONDOA in cancer metabolism. The observation that oncogenic MYC activity is dependent on MONDOA raises the possibility that disrupting MONDOA function or targeting MONDOA-regulated metabolic pathways may be an effective approach for treatment of MYC-driven tumors.

Carroll PA, Diolaiti D, McFerrin L, Gu H, Djukovic D, Du J, et al. Deregulated Myc requires MondoA/Mlx for metabolic reprogramming and tumorigenesis. Cancer Cell 2015;27:271–85.

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