{Reference Type}: Journal Article
{Title}: Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.
{Author}: Zhang Y;Wu MJ;Lu WC;Li YC;Chang CJ;Yang JY;
{Journal}: Cell Metab
{Volume}: 36
{Issue}: 1
{Year}: 2024 01 2
{Factor}: 31.373
{DOI}: 10.1016/j.cmet.2023.12.003
{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 β-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.