FBXW7 alleviates c-MYC repression of pyruvate carboxylase to support metabolic flexibility

Metabolic flexibility, or the ability to adapt to environmental fluctuations, is key to the survival and growth of all living organisms. In mammals, the pathways supporting cell proliferation in nutrient-limiting conditions have not been fully elucidated, although cancers are known to display metabolic dependencies that can be targeted for therapy. Here, we combine systematic nutrient and genome-wide CRISPR/Cas9 screening to provide a comprehensive map of the signaling and metabolic pathways that support cell proliferation in glutamine-limited conditions. We focus on pyruvate anaplerosis and discover a mechanism by which the tumor suppressor FBXW7 controls a MYC-dependent cluster of epigenetic repressors that bind the pyruvate carboxylase (PC) promoter, leading to histone deacetylation, reduced PC expression and glutamine addiction. Our work sheds light on the molecular mechanisms that support metabolic flexibility, and on the nutrients and pathways involved in glutamine dependency, a hallmark of several cancers.