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

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