Journal
CELL REPORTS
Volume 14, Issue 4, Pages 920-931Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.12.086
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Funding
- Fonds de Recherche du Quebec - Sante (FRQS)
- McGill Integrated Cancer Research Training Program (MICRTP)
- Michael D'Avirro Fellowship in Molecular Oncology (McGill University)
- Canadian Institutes of Health Research (CIHR)
- FRQS
- MICRTP
- CIHR [MOP-273977, MOP-64275, MOP-106603]
- Terry Fox Research Institute [TFF-116128]
- Terry Fox Research Institute (Metabolomics Core Facility)
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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.
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