Control of cyclin D1 and breast tumorigenesis by the EglN2 prolyl hydroxylase.
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 nonessential 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.
Zhang
Qing
Q
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Gu
Jinming
J
Li
Lianjie
L
Liu
Jiayun
J
Luo
Biao
B
Cheung
Hiu-Wing
HW
Boehm
Jesse S
JS
Ni
Min
M
Geisen
Christoph
C
Root
David E
DE
Polyak
Kornelia
K
Brown
Myles
M
Richardson
Andrea L
AL
Hahn
William C
WC
Kaelin
William G
WG
Bommi-Reddy
Archana
A
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008822:Mice, Transgenic; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D019938:Cyclin D1; D049308:Dioxygenases; D011393:Procollagen-Proline Dioxygenase