HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity

Ching Ying Kuo, Chun Ting Cheng, Peifeng Hou, Yi Pei Lin, Huimin Ma, Yiyin Chung, Kevin Chi, Yuan Chen, Wei Li, Hsing-Jien Kung, David K. Ann

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Up-regulation of hypoxia-inducible factor-1β (HIF-1β), even in normoxia, is a common feature of solid malignancies. However, the mechanisms of increased HIF-1β 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 β-ketoglutarate (β-KG) analogue, transiently stabilizes HIF-1β 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-1β induction and reductive carboxylation pathway activation. Both HIF-1β 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 β-KG, which in turn stabilizes HIF-1β 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-1β is indispensable for breast cancer tumorigenicity.

Original languageEnglish (US)
Pages (from-to)34052-34069
Number of pages18
JournalOncotarget
Volume7
Issue number23
DOIs
StatePublished - Jun 7 2016
Externally publishedYes

Keywords

  • Breast cancer tumorigenicity
  • Hypoxia-inducible factor-1α (HIF-1α)
  • Metabolic reprogramming
  • Mitochondria
  • α-ketoglutarate

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Kuo, C. Y., Cheng, C. T., Hou, P., Lin, Y. P., Ma, H., Chung, Y., Chi, K., Chen, Y., Li, W., Kung, H-J., & Ann, D. K. (2016). HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity. Oncotarget, 7(23), 34052-34069. https://doi.org/10.18632/oncotarget.8570