No abstract

SUMMARY 2-Oxoglutarate-dependent dioxygenases, including the EglN prolyl hydroxylases that regulate HIF, can be inhibited with drug-like molecules. EglN2 is estrogen-inducible in breast carcinoma cells and the lone Drosophila EglN interacts genetically with Cyclin D1. Although EglN2 is a non-essential gene we found that EglN2 inactivation decreases Cyclin D1 levels and suppresses mammary gland proliferation in vivo. Regulation of Cyclin D1 is a specific attribute of EglN2 among the EglN proteins and is HIF-independent. Loss of EglN2 catalytic activity inhibits estrogen-dependent breast cancer tumorigenesis and can be rescued by exogenous Cyclin D1. EglN2 depletion also impairs the fitness of lung, brain, and hematopoietic cancer lines. These findings support the exploration of EglN2 inhibitors as therapeutics for estrogen-dependent breast cancer and other malignancies. SIGNIFICANCE Cyclin D1 plays an important role in many cancers, including breast cancer. The observations described herein predict that inhibiting EglN2 catalytic activity will diminish Cyclin D1 levels in cancer cells and impair their ability to proliferate in vivo. Notably, EglN2 is estrogen-inducible and loss of either EglN2 or Cyclin D1 leads to mammary gland hypoproliferation. Therefore the relationship between EglN2 and Cyclin D1 might be especially relevant in hormone-sensitive breast cancer, where new therapies are needed for women who become refractory to estrogen antagonists. EglN2 appears to be an attractive drug target because EglN2 is not essential in mammals and it has already been established that enzymes of this class can be inhibited with drug-like small organic molecules.