The PGC-1a/ERRa Axis Represses One-Carbon Metabolism and Promotes Sensitivity to Anti-Folate Therapy in Breast Cancer [ChIP-Seq]

Reprogramming of cellular metabolism plays a central role in fuelling malignant transformation, and AMPK as well as the PGC-1a/ERRa 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-1a/ERRa and promotes the binding of ERRa to its cognate sites. Unexpectedly, the data also reveal that ERRa, in concert with PGC-1a, negatively regulates the expression of several one-carbon metabolism genes resulting in substantial perturbations in purine biosynthesis. This PGC-1a/ERRa-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-1a/ERRa 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. We used microarrays to detail the global programme of gene expression following AMPK activation by AICAR in BT474 breast cancer cells. Overall design: BT474 breast cancer cells were treated for 24h with vehicle or the AMPK activator AICAR and RNA was then purified for microarray analysis. Experiments were performed in duplicate for each condition.