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Transcriptional reprogramming of cellular metabolism is a hallmark of cancer. However, systematic approaches to study the role of transcriptional regulators (TRs) in mediating cancer metabolic rewiring are missing. Here, we chart a genome-scale map of TR-metabolite associations in human cells using a combined computational-experimental framework for large-scale metabolic profiling of adherent cell lines. By integrating intracellular metabolic profiles of 54 cancer cell lines with transcriptomic and proteomic data, we unraveled a large space of associations between TRs and metabolic pathways. We found a global regulatory signature coordinating glucose- and one-carbon metabolism, suggesting that regulation of carbon metabolism in cancer may be more diverse and flexible than previously appreciated. Here, we demonstrate how this TR-metabolite map can serve as a resource to predict TRs potentially responsible for metabolic transformation in patient-derived tumor samples, opening new opportunities in understanding disease etiology, selecting therapeutic treatments and in designing modulators of cancer-related TRs.

Metabolic profiling of cancer cells reveals genome-wide crosstalk between transcriptional regulators and metabolism