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

6 Citations (Scopus)

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
Pages (from-to)34052-34069
Number of pages18
JournalOncotarget
Volume7
Issue number23
DOIs
Publication statusPublished - Jun 7 2016

Fingerprint

Hypoxia-Inducible Factor 1
Breast Neoplasms
Fumarates
Succinic Acid
Hypoxia-Inducible Factor-Proline Dioxygenases
Neoplasms
Pluripotent Stem Cells
Glycolysis
alpha-ketoglutaric acid
Respiration
Up-Regulation
Cell Membrane
Oxygen

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Kuo, C. Y., Cheng, C. T., Hou, P., Lin, Y. P., Ma, H., Chung, Y., ... 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

HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity. / Kuo, Ching Ying; Cheng, Chun Ting; Hou, Peifeng; Lin, Yi Pei; Ma, Huimin; Chung, Yiyin; Chi, Kevin; Chen, Yuan; Li, Wei; Kung, Hsing Jien; Ann, David K.

In: Oncotarget, Vol. 7, No. 23, 07.06.2016, p. 34052-34069.

Research output: Contribution to journalArticle

Kuo, CY, Cheng, CT, Hou, P, Lin, YP, Ma, H, Chung, Y, Chi, K, Chen, Y, Li, W, Kung, HJ & Ann, DK 2016, 'HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity', Oncotarget, vol. 7, no. 23, pp. 34052-34069. https://doi.org/10.18632/oncotarget.8570
Kuo, Ching Ying ; Cheng, Chun Ting ; Hou, Peifeng ; Lin, Yi Pei ; Ma, Huimin ; Chung, Yiyin ; Chi, Kevin ; Chen, Yuan ; Li, Wei ; Kung, Hsing Jien ; Ann, David K. / HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity. In: Oncotarget. 2016 ; Vol. 7, No. 23. pp. 34052-34069.
@article{f1f087908e2140ae88d05cde3281316a,
title = "HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity",
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.",
keywords = "Breast cancer tumorigenicity, Hypoxia-inducible factor-1α (HIF-1α), Metabolic reprogramming, Mitochondria, α-ketoglutarate",
author = "Kuo, {Ching Ying} and Cheng, {Chun Ting} and Peifeng Hou and Lin, {Yi Pei} and Huimin Ma and Yiyin Chung and Kevin Chi and Yuan Chen and Wei Li and Kung, {Hsing Jien} and Ann, {David K.}",
year = "2016",
month = "6",
day = "7",
doi = "10.18632/oncotarget.8570",
language = "English",
volume = "7",
pages = "34052--34069",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "23",

}

TY - JOUR

T1 - HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity

AU - Kuo, Ching Ying

AU - Cheng, Chun Ting

AU - Hou, Peifeng

AU - Lin, Yi Pei

AU - Ma, Huimin

AU - Chung, Yiyin

AU - Chi, Kevin

AU - Chen, Yuan

AU - Li, Wei

AU - Kung, Hsing Jien

AU - Ann, David K.

PY - 2016/6/7

Y1 - 2016/6/7

N2 - 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.

AB - 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.

KW - Breast cancer tumorigenicity

KW - Hypoxia-inducible factor-1α (HIF-1α)

KW - Metabolic reprogramming

KW - Mitochondria

KW - α-ketoglutarate

UR - http://www.scopus.com/inward/record.url?scp=84973664240&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84973664240&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.8570

DO - 10.18632/oncotarget.8570

M3 - Article

C2 - 27058900

AN - SCOPUS:84973664240

VL - 7

SP - 34052

EP - 34069

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 23

ER -