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

Reprogramming of cellular metabolism plays a central role in fueling malignant transformation, and AMPK and the PGC-1 alpha/ERR alpha 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-1 alpha/ERR alpha and promotes the binding of ERR alpha to its cognate sites. Unexpectedly, the data also reveal that ERR alpha, in concert with PGC-1 alpha, negatively regulates the expression of several one-carbon metabolism genes, resulting in substantial perturbations in purine biosynthesis. This PGC-1 alpha/ERR alpha-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-1 alpha/ERR alpha 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.