ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming
Prachi Mishra, … , Nagireddy Putluri, Stefan Ambs
Prachi Mishra, … , Nagireddy Putluri, Stefan Ambs
Published November 27, 2017
Citation Information: J Clin Invest. 2018;128(1):323-340. https://doi.org/10.1172/JCI93815.
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Research Article Metabolism Oncology

ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming

Abstract

Metabolic reprogramming in breast tumors is linked to increases in putative oncogenic metabolites that may contribute to malignant transformation. We previously showed that accumulation of the oncometabolite, 2-hydroxyglutarate (2HG), in breast tumors was associated with MYC signaling, but not with isocitrate dehydrogenase (IDH) mutations, suggesting a distinct mechanism for increased 2HG in breast cancer. Here, we determined that D-2HG is the predominant enantiomer in human breast tumors and show that the D-2HG–producing mitochondrial enzyme, alcohol dehydrogenase, iron-containing protein 1 (ADHFE1), is a breast cancer oncogene that decreases patient survival. We found that MYC upregulates ADHFE1 through changes in iron metabolism while coexpression of both ADHFE1 and MYC strongly enhanced orthotopic tumor growth in MCF7 cells. Moreover, ADHFE1 promoted metabolic reprogramming with increased formation of D-2HG and reactive oxygen, a reductive glutamine metabolism, and modifications of the epigenetic landscape, leading to cellular dedifferentiation, enhanced mesenchymal transition, and phenocopying alterations that occur with high D-2HG levels in cancer cells with IDH mutations. Together, our data support the hypothesis that ADHFE1 and MYC signaling contribute to D-2HG accumulation in breast tumors and show that D-2HG is an oncogenic metabolite and potential driver of disease progression.

Authors

Prachi Mishra, Wei Tang, Vasanta Putluri, Tiffany H. Dorsey, Feng Jin, Fang Wang, Donewei Zhu, Lauren Amable, Tao Deng, Shaofei Zhang, J. Keith Killian, Yonghong Wang, Tsion Z. Minas, Harry G. Yfantis, Dong H. Lee, Arun Sreekumar, Michael Bustin, Wei Liu, Nagireddy Putluri, Stefan Ambs

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Figure 10

ChIP-seq analysis of H3K4me3 in ADHFE1- and MYC-overexpressing MCF7 cells.

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ChIP-seq analysis of H3K4me3 in ADHFE1- and MYC-overexpressing MCF7 cell...
Trimethylation of histone H3 lysine 4 (H3K4me3) is globally increased in promoter regions of genes regulating epithelial-to-mesenchymal transition (EMT) (A), the axon guidance pathway (B), and stemness (C) in MCF7 cells overexpressing either MYC or ADHFE1 (FDR < 5% for each pathway, compared with vector control cells). Examples for EMT pathway, ZEB1 and CDH2 (N-cadherin); axon guidance, SEMA3A and SEMA3D; and stem cell markers, SOX9 and FGFR2. H3K4me3 is significantly increased in the promoter region for each of the shown genes, with the exception of ZEB1, comparing ADHFE1-overexpressing versus vector control cells (FDR < 5%). EMT pathway: 344 genes. Axon guidance pathway: 127 genes. Pluripotency of stem cells pathway: 138 genes. Shown is the summarized read coverage for triplicate experiments of the ChIP-seq data. TSS, transcription start site. (D) Upregulation of ADHFE1 and D-2HG formation in breast tumors and their relationship to EMT and metabolic reprogramming. MYC increases D-2HG formation by increasing both substrate and iron availability for the iron-containing enzyme, ADHFE1. ADHFE1 and D-2HG induce a reductive glutamine metabolism, ROS, and histone methylation at H3K4me3, leading to increased acetyl-CoA and fatty acid synthesis and EMT. α-KG, α-ketoglutarate; 4-HB, 4-hydroxybutyrate; SSA, succinic semialdehyde.