Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.
Cell Metab
; 36(1): 193-208.e8, 2024 01 02.
Article
en En
| MEDLINE
| ID: mdl-38171333
ABSTRACT
Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid ß-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.
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Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama Triple Negativas
Idioma:
En
Revista:
Cell Metab
Asunto de la revista:
METABOLISMO
Año:
2024
Tipo del documento:
Article