Journal Article

ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming

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

2018

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Alcohol dehydrogenase / Alcohol Oxidoreductases - genetics / Alcohol Oxidoreductases - metabolism / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cell Dedifferentiation / Cellular Reprogramming / Dehydrogenases / Development and progression / Enantiomers / Epigenetic inheritance / Epigenetics / Female / Genetic aspects / Glutamine / Glutarates - metabolism / Humans / Hypotheses / Isocitrate dehydrogenase / Mass spectrometry / MCF-7 Cells / Metabolism / Metabolites / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / Mutation / Myc protein / Oncogenes / Physiological aspects / Protein expression / Protein turnover / Proteins / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins c-myc - metabolism / Reactive Oxygen Species - metabolism / Scientific imaging / Signal Transduction / Survival analysis / Tumors