The PGC-1/ERR Axis Represses One-Carbon Metabolism and Promotes Sensitivity to Anti-Folate Therapy in Breast Cancer [Microarray expression]

Reprogramming of cellular metabolism plays a central role in fuelling malignant transformation, and AMPK as well as the PGC-1/ERR axis are key regulators of this process. Intersection of gene expression and binding event datasets in breast cancer cells shows that activation of AMPK significantly increases the expression of PGC-1/ERR and promotes the binding of ERR to its cognate sites. Unexpectedly, the data also reveal that ERR, in concert with PGC-1, negatively regulates the expression of several one-carbon metabolism genes resulting in substantial perturbations in purine biosynthesis. This PGC-1/ERR-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/ERR 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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Audet-Walsh É, Papadopoli DJ, Gravel SP, Yee T, Bridon G, Caron M, Bourque G, Giguère V, St-Pierre J