EglN2 associates with the NRF1-PGC1α complex and controls mitochondrial function in breast cancer.

Abstract

The EglN2/PHD1 prolyl hydroxylase is an important oxygen sensor contributing to breast tumorigenesis. Emerging studies suggest that there is functional cross talk between oxygen sensing and mitochondrial function, both of which play an essential role for sustained tumor growth. However, the potential link between EglN2 and mitochondrial function remains largely undefined. Here, we show that EglN2 depletion decreases mitochondrial respiration in breast cancer under normoxia and hypoxia, which correlates with decreased mitochondrial DNA in a HIF1/2α-independent manner. Integrative analyses of gene expression profile and genomewide binding of EglN2 under hypoxic conditions reveal nuclear respiratory factor 1 (NRF1) motif enrichment in EglN2-activated genes, suggesting NRF1 as an EglN2 binding partner. Mechanistically, by forming an activator complex with PGC1α and NRF1 on chromatin, EglN2 promotes the transcription of ferridoxin reductase (FDXR) and maintains mitochondrial function. In addition, FDXR, as one of effectors for EglN2, contributes to breast tumorigenesis in vitro and in vivo. Our findings suggest that EglN2 regulates mitochondrial function in ERα-positive breast cancer.

• Authors: Jing Zhang, Chengyang Wang, Xi Chen, Mamoru Takada, Cheng Fan, Xingnan Zheng, Haitao Wen, Yong Liu, Chenguang Wang, Richard G Pestell, Katherine M Aird, William G Kaelin Jr, Xiaole Shirley Liu, Qing Zhang
• Journal: The EMBO journal (EMBO J) Vol. 34 Issue 23 Pg. 2953-70 (Dec 02 2015) ISSN: 1460-2075 [Electronic] England
• PMID: 26492917 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors.

Chemical References

• NF-E2-Related Factor 1
• PPARGC1A protein, human
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Transcription Factors
• EGLN2 protein, human
• Hypoxia-Inducible Factor-Proline Dioxygenases

Topics

• Breast Neoplasms (genetics, metabolism)
• Cell Line, Tumor
• Female
• Humans
• Hypoxia-Inducible Factor-Proline Dioxygenases (genetics, metabolism)
• Mitochondria (metabolism)
• NF-E2-Related Factor 1 (genetics, metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Protein Binding
• Transcription Factors (genetics, metabolism)