Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia

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Title: Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia
Authors: Peng, F
Wang, J
Fan, W
Meng, Y
Li, M
Li, T
Cui, B
Wang, H
Zhao, Y
An, F
Guo, T
Liu, X
Zhang, L
Lv, L
Lv, D
Xu, L
Xie, J
Lin, W
Lam, EW
Xu, J
Liu, Q
Item Type: Journal Article
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 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. Appropriately, H19 and PDK1 expression exhibits strong correlations in primary breast carcinomas. Importantly, H19 acting as a competitive endogenous RNA (ceRNA) sequesters miRNA let-7 to release HIF-1α, leading to an increase in PDK1 expression. Intriguingly, aspirin dramatically attenuates glycolysis and cancer stem-like characteristics by suppressing both H19 and PDK1. Collectively, these novel findings demonstrate that the glycolysis gatekeeper PDK1 plays a critical role in BCSC reprogramming and provides a potential therapeutic strategy for breast malignancy.
Issue Date: 6-Nov-2017
Date of Acceptance: 30-Aug-2017
ISSN: 0950-9232
Publisher: Nature Publishing Group
Start Page: 1062
End Page: 1074
Journal / Book Title: Oncogene
Volume: 37
Copyright Statement: © The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit by/4.0/
Sponsor/Funder: Cancer Research UK
Breast Cancer Now
Breast Cancer Now
Breast Cancer Now
Commonwealth Scholarship Commission
Medical Research Council (MRC)
Funder's Grant Number: C37/A12011
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Genetics & Heredity
1112 Oncology And Carcinogenesis
1103 Clinical Sciences
Oncology & Carcinogenesis
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine

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