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Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia.
Oncogene 2018; 37(8):1062-1074O

Abstract

Glycolysis is critical for cancer stem cell reprogramming; however, the underlying regulatory mechanisms remain elusive. Here, we show that pyruvate dehydrogenase kinase 1 (PDK1) is enriched in breast cancer stem cells (BCSCs), whereas depletion of PDK1 remarkably diminishes ALDH+ subpopulations, decreases stemness-related transcriptional factor expression, and inhibits sphere-formation ability and tumor growth. Conversely, high levels of PDK1 enhance BCSC properties and are correlated with poor overall survival. In mouse xenograft tumor, PDK1 is accumulated in hypoxic regions and activates glycolysis to promote stem-like traits. Moreover, through screening hypoxia-related long non-coding RNAs (lncRNAs) in PDK1-positive tissue, we find that lncRNA H19 is responsible for glycolysis and BCSC maintenance. Furthermore, H19 knockdown decreases PDK1 expression in hypoxia, and ablation of PDK1 counteracts H19-mediated glycolysis and self-renewal ability in vitro and in vivo. Accordingly, H19 and PDK1 expression exhibits strong correlations in primary breast carcinomas. H19 acting as a competitive endogenous RNA sequesters miRNA let-7 to release Hypoxia-inducible factor 1α, leading to an increase in PDK1 expression. Lastly, aspirin markedly attenuates glycolysis and cancer stem-like characteristics by suppressing both H19 and PDK1. Thus, these novel findings demonstrate that the glycolysis gatekeeper PDK1 has a critical role in BCSC reprogramming and provides a potential therapeutic strategy for breast malignancy.

Authors+Show Affiliations

Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.Department of Pathology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. Internal Medicine Department of Oncology, the Second Affiliated Hospital of Dalian Medical University, Dalian, China.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.Dalian Maternal and Child Care Service Centre, Dalian, Liaoning, China.Department of Surgery and Cancer, Imperial College London, London, UK.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29106390

Citation

Peng, F, et al. "Glycolysis Gatekeeper PDK1 Reprograms Breast Cancer Stem Cells Under Hypoxia." Oncogene, vol. 37, no. 8, 2018, pp. 1062-1074.
Peng F, Wang JH, Fan WJ, et al. Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia. Oncogene. 2018;37(8):1062-1074.
Peng, F., Wang, J. H., Fan, W. J., Meng, Y. T., Li, M. M., Li, T. T., ... Liu, Q. (2018). Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia. Oncogene, 37(8), pp. 1062-1074. doi:10.1038/onc.2017.368.
Peng F, et al. Glycolysis Gatekeeper PDK1 Reprograms Breast Cancer Stem Cells Under Hypoxia. Oncogene. 2018 02 22;37(8):1062-1074. PubMed PMID: 29106390.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia. AU - Peng,F, AU - Wang,J-H, AU - Fan,W-J, AU - Meng,Y-T, AU - Li,M-M, AU - Li,T-T, AU - Cui,B, AU - Wang,H-F, AU - Zhao,Y, AU - An,F, AU - Guo,T, AU - Liu,X-F, AU - Zhang,L, AU - Lv,L, AU - Lv,D-K, AU - Xu,L-Z, AU - Xie,J-J, AU - Lin,W-X, AU - Lam,E W-F, AU - Xu,J, AU - Liu,Q, Y1 - 2017/11/06/ PY - 2017/01/03/received PY - 2017/08/24/revised PY - 2017/08/30/accepted PY - 2017/11/7/pubmed PY - 2019/3/7/medline PY - 2017/11/7/entrez SP - 1062 EP - 1074 JF - Oncogene JO - Oncogene VL - 37 IS - 8 N2 - Glycolysis is critical for cancer stem cell reprogramming; however, the underlying regulatory mechanisms remain elusive. Here, we show that pyruvate dehydrogenase kinase 1 (PDK1) is enriched in breast cancer stem cells (BCSCs), whereas depletion of PDK1 remarkably diminishes ALDH+ subpopulations, decreases stemness-related transcriptional factor expression, and inhibits sphere-formation ability and tumor growth. Conversely, high levels of PDK1 enhance BCSC properties and are correlated with poor overall survival. In mouse xenograft tumor, PDK1 is accumulated in hypoxic regions and activates glycolysis to promote stem-like traits. Moreover, through screening hypoxia-related long non-coding RNAs (lncRNAs) in PDK1-positive tissue, we find that lncRNA H19 is responsible for glycolysis and BCSC maintenance. Furthermore, H19 knockdown decreases PDK1 expression in hypoxia, and ablation of PDK1 counteracts H19-mediated glycolysis and self-renewal ability in vitro and in vivo. Accordingly, H19 and PDK1 expression exhibits strong correlations in primary breast carcinomas. H19 acting as a competitive endogenous RNA sequesters miRNA let-7 to release Hypoxia-inducible factor 1α, leading to an increase in PDK1 expression. Lastly, aspirin markedly attenuates glycolysis and cancer stem-like characteristics by suppressing both H19 and PDK1. Thus, these novel findings demonstrate that the glycolysis gatekeeper PDK1 has a critical role in BCSC reprogramming and provides a potential therapeutic strategy for breast malignancy. SN - 1476-5594 UR - https://www.unboundmedicine.com/medline/citation/29106390/Glycolysis_gatekeeper_PDK1_reprograms_breast_cancer_stem_cells_under_hypoxia_ L2 - http://dx.doi.org/10.1038/onc.2017.368 DB - PRIME DP - Unbound Medicine ER -