EglN2 associates with the NRF1-PGC1α complex and controls mitochondrial function in breast cancer.
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.
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Jing
J
Zhang
Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China.
Chengyang
C
Wang
Department of Molecular and Cellular Biology, The Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA.
Xi
X
Chen
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Mamoru
M
Takada
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Cheng
C
Fan
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Xingnan
X
Zheng
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA Department of Surgery, University of North Carolina, Chapel Hill, NC, USA.
Haitao
H
Wen
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Yong
Y
Liu
Program of Radiation Protection and Drug Discovery, Institute of Radiation Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China.
Chenguang
C
Wang
Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Richard G
RG
Pestell
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA.
Katherine M
KM
Aird
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Howard Hughes Medical Institute, Chevy Chase, MD, USA.
William G
WG
Kaelin
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA, USA.
Xiaole Shirley
XS
Liu
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA qing_zhang@med.unc.edu.
Qing
Q
Zhang
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D051265:NF-E2-Related Factor 1 / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051265:NF-E2-Related Factor 1; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
EglN2; NRF1; hypoxia; mitochondria; tumorigenesis