Original Article

Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia

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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.

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Acknowledgements

We thank Quentin Liu’s lab members for their critical commends and technical support. This work is supported by Innovative Research Team in University of Ministry of Education of China (No. IRT13049), National Natural Science Foundation of China (No. 81630005 and No. 81573025 to QL, No. 81201686 to JX, No. 81602588 to L-ZX, No. 81502579 to Z-JH, No. 81602585 to F-MZ), the Liaoning (NSF2014029102 to QL, NSF 2015020264 to JX, 201601231 to L-ZX), Dalian high-level talent innovation program (2016RD12 to QL). Eric W-F Lam’s work is supported by CRUK (A12011) and Breast Cancer Now (2012 May PR070; 2012 Nov PhD016).

Author information

Author notes

    • F Peng
    • , J-H Wang
    •  & W-J Fan

    These authors contributed equally to this work.

Affiliations

  1. Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China

    • F Peng
    • , W-J Fan
    • , Y-T Meng
    • , M-M Li
    • , T-T Li
    • , B Cui
    • , H-F Wang
    • , F An
    • , X-F Liu
    • , L Zhang
    • , D-K Lv
    • , L-Z Xu
    • , J-J Xie
    • , J Xu
    •  & Q Liu
  2. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China

    • F Peng
    • , W-J Fan
    • , Y-T Meng
    • , M-M Li
    •  & Q Liu
  3. Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, China

    • J-H Wang
    •  & Y Zhao
  4. Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China

    • T Guo
  5. Department of Pathology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China

    • L Lv
  6. Internal Medicine Department of Oncology, the Second Affiliated Hospital of Dalian Medical University, Dalian, China

    • L-Z Xu
  7. Dalian Maternal and Child Care Service Centre, Dalian, Liaoning, China

    • W-X Lin
  8. Department of Surgery and Cancer, Imperial College London, London, UK

    • E W-F Lam

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Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to J Xu or Q Liu.

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