Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia

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.

Plasminogen Activator Inhibitor 1 (PAI1) Promotes Actin Cytoskeleton Reorganization and Glycolytic Metabolism in Triple-Negative Breast Cancer

“…Reprogramming of cellular metabolism represents a hallmark feature of cancer with malignant cells frequently shifting to glycolytic metabolism (41). Breast cancers upregulate glycolytic enzymes relative to normal breast tissue and benign breast lesions, and glycolytic metabolism correlates with worse outcomes (42,43). Mechanisms underlying a switch from oxidative to glycolytic metabolism in cancer cells remain incompletely defined.…”

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

“…H19 sponges miRNA tumor suppressor, let-7, facilitating a concomitant increase in the breast CSC-enriched pluripotency factor LIN28. The sponging of let-7 by H19 also leads to the increased expression of the glycolytic enzyme pyruvate dehydrogenase kinase 1 (PDK1), which promotes the metabolic reprogramming of breast CSCs [62].…”

PDK1 promotes ovarian cancer metastasis by modulating tumor-mesothelial adhesion, invasion, and angiogenesis via α5β1 integrin and JNK/IL-8 signaling

“…Four PDK isoenzymes (PDK1-4) have been identified in humans, with PDK1 being the best-studied isoenzyme [10][11][12] . The metabolic switch mediated by PDK1 has been shown to support malignant phenotypes in vitro such as headand-neck squamous cell carcinoma (HNSC) resistance to hypoxia-induced cell death 13 , breast cancer cell anoikis resistance 14 , oncogene-induced senescence in melanomas 15 , and breast cancer stem cell reprogramming 16 . Knockdown of PDK1 is reported to impede tumor growth in nude mice in HNSC, melanoma, and breast cancer cells 13,15,16 .…”

“…The metabolic switch mediated by PDK1 has been shown to support malignant phenotypes in vitro such as headand-neck squamous cell carcinoma (HNSC) resistance to hypoxia-induced cell death 13 , breast cancer cell anoikis resistance 14 , oncogene-induced senescence in melanomas 15 , and breast cancer stem cell reprogramming 16 . Knockdown of PDK1 is reported to impede tumor growth in nude mice in HNSC, melanoma, and breast cancer cells 13,15,16 . Tyrosine phosphorylation activates PDK1 to promote the Warburg effect and in vivo tumor growth in leukemia and lung cancer cells 17 .…”