| First Author | Zhang Y | Year | 2024 |
| Journal | Cell Metab | Volume | 36 |
| Issue | 1 | Pages | 193-208.e8 |
| PubMed ID | 38171333 | Mgi Jnum | J:351130 |
| Mgi Id | MGI:7574015 | Doi | 10.1016/j.cmet.2023.12.003 |
| Citation | Zhang Y, et al. (2024) Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer. Cell Metab 36(1):193-208.e8 |
| abstractText | 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 beta-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. |
