title: HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity.
abstract: Up-regulation of hypoxia-inducible factor-1α (HIF-1α), even in normoxia, is a common feature of solid malignancies. However, the mechanisms of increased HIF-1α abundance, and its role in regulating breast cancer plasticity are not fully understood. We have previously demonstrated that dimethyl-2-ketoglutarate (DKG), a widely used cell membrane-permeable α-ketoglutarate (α-KG) analogue, transiently stabilizes HIF-1α by inhibiting prolyl hydroxylase 2. Here, we report that breast cancer tumorigenicity can be acquired through prolonged treatment with DKG. Our results indicate that, in response to prolonged DKG treatment, mitochondrial respiration becomes uncoupled, leading to the accumulation of succinate and fumarate in breast cancer cells. Further, we found that an early increase in the oxygen flux rate was accompanied by a delayed enhancement of glycolysis. Together, our results indicate that these events trigger a dynamic enrichment for cells with pluripotent/stem-like cell markers and tumorsphere-forming capacity. Moreover, DKG-mediated metabolic reprogramming results in HIF-1α induction and reductive carboxylation pathway activation. Both HIF-1α accumulation and the tumor-promoting metabolic state are required for DKG-promoted tumor repopulation capacity in vivo. Our data suggest that mitochondrial adaptation to DKG elevates the ratio of succinate or fumarate to α-KG, which in turn stabilizes HIF-1α and reprograms breast cancer cells into a stem-like state. Therefore, our results demonstrate that metabolic regulation, with succinate and/or fumarate accumulation, governs the dynamic transition of breast cancer tumorigenic states and we suggest that HIF-1α is indispensable for breast cancer tumorigenicity.
authors.affiliation: Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA.
authors.forename: Ching-Ying
authors.initials: CY
authors.lastname: Kuo
authors.affiliation: Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA.|Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA, USA.
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Cheng
authors.affiliation: Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA.|Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.|Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, China.
authors.forename: Peifeng
authors.initials: P
authors.lastname: Hou
authors.affiliation: Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: Yi-Pei
authors.initials: YP
authors.lastname: Lin
authors.affiliation: Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Ma
authors.affiliation: Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA.
authors.forename: Yiyin
authors.initials: Y
authors.lastname: Chung
authors.affiliation: Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Chi
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan, ROC.|Institute of Molecular and Genomic Medicine, National Health Research Institutes, Taiwan, ROC.
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.affiliation: Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA.|Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D005260:Female; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000494:pharmacology*; D016688:Mice, Inbred NOD; D008928:Mitochondria / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids
keywords: breast cancer tumorigenicity; hypoxia-inducible factor-1α (HIF-1α); metabolic reprogramming; mitochondria; α-ketoglutarate