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MUC1-C integrates induction of aerobic glycolysis with suppression of oxidative phosphorylation in cancer stem cells

ABSTRACT: The MUC1-C protein evolved in mammals for adaptation of barrier tissues to loss of homeostasis. Prolonged activation of MUC1-C in settings of chronic inflammation promotes lineage plasticity, epigenetic reprogramming and the cancer stem cell (CSC) state. The effects of MUC1-C on the metabolism of CSCs remain unexplored. The present studies performed on purified populations of triple-negative breast cancer (TNBC) CSCs demonstrate that MUC1-C integrates the capacity for self-renewal with the activation of aerobic glycolysis. We show that MUC1-C is essential for (i) CSC mammosphere formation and tumorigenicity and (ii) activation of GLUT1, HK2 and other glycolytic genes. We further show that MUC1-C activates nuclear genes that encode components of mitochondrial Complexes II-V of the electron transfer chain (ETC). Of importance, MUC1-C also represses mitochondrial DNA (mtDNA) genes encoding components of Complexes I-V. The observed involvement of MUC1-C in the suppression of mtDNA genes is explained by MUC1-C-mediated (i) downregulation of the mitochondrial transcription factor A (TFAM), which is required for mtDNA transcription, and (ii) induction of the mitochondrial transcription termination factor 3 (mTERF3). In support of this pathway to suppress mitochondrial ROS production, targeting MUC1-C increases (i) mtDNA gene transcription, (ii) superoxide levels and (iii) loss of self-renewal capacity. These findings indicate that MUC1-C regulates CSC self-renewal and redox balance by integrating activation of glycolysis with suppression of oxidative phosphorylation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222377 | GEO | 2023/10/11

REPOSITORIES: GEO

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Project description:Project 1: The deregulation of the actin cytoskeleton has been extensively studied in metastatic dissemination. However, the post-dissemination role of the actin cytoskeleton dysregulation is poorly understood. Here we report that fascin, an actin-bundling protein, promotes lung cancer metastatic colonization by augmenting metabolic stress resistance and mitochondrial OXPHOS. Fascin is directly recruited to mitochondria under metabolic stress to stabilize mitochondrial actin filaments (mtF-actin). Using unbiased metabolomics and proteomics approaches, we discovered that fascin-mediated mtF-actin remodeling promotes mitochondrial OXPHOS by increasing the biogenesis of respiratory Complex I. Mechanistically, fascin and mtF-actin controls the homeostasis of mtDNA to promote mitochondrial OXPHOS. The disruption of mtFactin abrogates fascin-mediated lung cancer metastasis. Conversely, restoration of mitochondrial respiration using yeast NDI1 in fascin depleted cancer cells is able to rescue lung metastasis. Our findings indicate that the dysregulated actin cytoskeleton in metastatic lung cancer could be targeted to rewire mitochondrial metabolism and to prevent metastatic recurrence. Project 2: There is a pool of mitochondrial dNTP in the cell maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis in slow-cycling and post-mitotic cells. The role of the mitochondrial deoxynucleoside salvage pathway in tumor initiation and progression is poorly understood. Here, we investigated the role of the mitochondrial deoxyguanosine kinase (DGUOK), a rate-limiting enzyme in the mitochondrial deoxynucleoside salvage pathway, in the self-renewal of lung adenocarcinoma cancer stem-like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis and CSC self-renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory Complex I and mitochondrial OXPHOS, which in turn regulates CSC self-renewal through AMPK-YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK depleted lung cancer cells using NDI1, a single subunit yeast NADH : ubiquinone oxidoreductase, was able to rescue AMPK-YAP1 signaling and CSC stemness. Genetic targeting of DGUOK using doxycycline-inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC-mediated therapy resistance and metastatic recurrence.

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MUC1-C integrates induction of aerobic glycolysis with suppression of oxidative phosphorylation in cancer stem cells

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