EglN2 associates with the NRF1‐PGC1α complex and controls mitochondrial function in breast cancer. (22nd October 2015)

• Record Type: Journal Article
• Authors: Zhang, Jing; Wang, Chengyang; Chen, Xi; Takada, Mamoru; Fan, Cheng; Zheng, Xingnan; Wen, Haitao; Liu, Yong; Wang, Chenguang; Pestell, Richard G; Aird, Katherine M; Kaelin, William G; Liu, Xiaole Shirley; Zhang, Qing
• Is Part Of: EMBO journal. Volume 34:Number 23(2015)
• Page Start: 2953
• Page End: 2970
• Publication Date: 2015-10-22
• Subjects: EglN2 -- hypoxia -- mitochondria -- NRF1 -- tumorigenesis; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201591437
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: While prolyl hydroxylase EglN2/PHD1 is well known for its role in oxygen‐dependent degradation of HIF1α, this work reports a HIF1‐independent role for EglN2 in regulating mitochondrial function via the formation of a transcription regulatory complex with PGC1α and NRF1. EglN2/PHD1 regulates mitochondrial function in ERα‐positive breast cancer under normoxia and hypoxia. The effect of EglN2 on mitochondrial function is HIF1/2α independent. EglN2 is an NRF1 binding partner that promotes transcription activation. EglN2 forms an activator complex with PGC1α and NRF1 on chromatin and promotes FDXR transcription. FDXR regulates mitochondrial function and contributes to breast tumorigenesis in vitro and in vivo . Abstract : While prolyl hydroxylase EglN2/PHD1 is well known for its role in oxygen‐dependent degradation of HIF1α, this work reports a HIF1‐independent role for EglN2 in regulating mitochondrial function via the formation of a transcription regulatory complex with PGC1α and NRF1.