The PGC-1α/ERRα Axis Represses One-Carbon Metabolism and Promotes Sensitivity to Anti-folate Therapy in Breast Cancer

• The PGC-1α/ERRα axis is a key effector of AMPK metabolic reprogramming in cancer
• The PGC-1α/ERRα axis represses folate cycle metabolism
• The PGC-1α/ERRα axis decreases purine biosynthesis
• The PGC-1α/ERRα axis sensitizes cells and tumors to anti-folate therapy

SummaryReprogramming of cellular metabolism plays a central role in fueling malignant transformation, and AMPK and the PGC-1α/ERRα axis are key regulators of this process. The intersection of gene-expression and binding-event datasets for breast cancer cells shows that activation of AMPK significantly increases the expression of PGC-1α/ERRα and promotes the binding of ERRα to its cognate sites. Unexpectedly, the data also reveal that ERRα, in concert with PGC-1α, negatively regulates the expression of several one-carbon metabolism genes, resulting in substantial perturbations in purine biosynthesis. This PGC-1α/ERRα-mediated repression of one-carbon metabolism promotes the sensitivity of breast cancer cells and tumors to the anti-folate drug methotrexate. These data implicate the PGC-1α/ERRα axis as a core regulatory node of folate cycle metabolism and further suggest that activators of AMPK could be used to modulate this pathway in cancer.

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