Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia

Fei Peng ,L-Z Xu,Bai Cui ,Eric W.‐F Lam ,Dekang Lv ,Li Lv ,H F Wang ,Wen‐Hsin Lin ,Yidan Zhao ,Yuting Meng ,Fengmin An ,M M Li ,Lei Zhang ,J H Wang ,X F Liu ,Jing Xie ,Tao Guo ,Jiao Xu ,T T Li ,Wenjun Fan ,Qiang Liu

doi:10.1038/onc.2017.368

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.

Highlights

Accumulating evidence indicates that a small subpopulation of cancer cells with stem cell properties have a strong correlation with enhanced tumorigenesis, metastasis, relapse and resistance to treatment.[1,2,3] These cancer stem cells (CSCs) display selfrenewing capacity and multilineage differentiation into various cell populations within the tumor mass.[4]
To identify the key glycolytic regulators involved in breast cancer stem-like cell reprogramming, the gene expression patterns of key glycolytic enzymes in the glucose metabolic pathway, including SLC2A1, HK2, PFK, PKM2, lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 (PDK1) (Supplementary Figure 1A), were compared between the CD44+ /CD24− and CD44−/CD24+ subpopulations from a previously published dataset.[35]
We examined PDK1 expression in breast cancer stem cells (BCSCs) purified from breast carcinoma cells through their mammosphere formation ability and ALDH+ cell sorting

Summary

Introduction

Accumulating evidence indicates that a small subpopulation of cancer cells with stem cell properties have a strong correlation with enhanced tumorigenesis, metastasis, relapse and resistance to treatment.[1,2,3] These cancer stem cells (CSCs) display selfrenewing capacity and multilineage differentiation into various cell populations within the tumor mass.[4] Reprogramming of energy metabolism is one of the hallmarks of cancer.[5] Various studies indicate that deranged metabolism, like aerobic glycolysis, is related to tumor growth and chemoresistance.[6] CSCs are highly plastic in terms of metabolic machinery and rely on either glycolysis or oxidative phosphorylation (OXPHOS).[7,8,9] As a key glucose metabolism process, glycolysis contributes to CSC maintenance in specific microenvironments, such as hypoxia and nutrient starvation.[10,11] Previous studies have revealed that

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Results

Conclusion