Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer

Yingsheng Zhang; Meng-Ju Wu; Wan-Chi Lu; Yi-Chuan Li; Chun Ju Chang; Jer-Yen Yang

doi:10.1016/j.cmet.2023.12.003

Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer

Cell Metab. 2024 Jan 2;36(1):193-208.e8. doi: 10.1016/j.cmet.2023.12.003.

Authors

Yingsheng Zhang¹, Meng-Ju Wu², Wan-Chi Lu³, Yi-Chuan Li⁴, Chun Ju Chang⁵, Jer-Yen Yang⁶

Affiliations

¹ Department of Medicine and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA 90048, USA. Electronic address: yingsheng.zhang@cshs.org.
² Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Departments of Medicine, Harvard Medical School, Boston, MA 02115, USA.
³ Institute of Biochemistry and Molecular Biology, China Medical University, Taichung 406040, Taiwan.
⁴ Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung 406040, Taiwan; Department of Biological Science and Technology, China Medical University, Taichung 406040, Taiwan.
⁵ Institute of Biochemistry and Molecular Biology, China Medical University, Taichung 406040, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung 406040, Taiwan. Electronic address: achang68@mail.cmu.edu.tw.
⁶ Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung 406040, Taiwan; Department of Biological Science and Technology, China Medical University, Taichung 406040, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung 406040, Taiwan. Electronic address: jyyang@cmu.edu.tw.

PMID: 38171333
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.

Keywords: EZH2; PKM2; SLC16A9; induced synthetic lethality; lineage plasticity; metabolic reprogramming.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carnitine
Cell Line, Tumor
Glycolysis
Humans
Synthetic Lethal Mutations
Triple Negative Breast Neoplasms* / metabolism

Substances

Carnitine