Many transformed cells and embryonic stem cells are dependent on the biosynthesis of the universal methyl-donor S-adenosylmethionine (SAM) from methionine by the enzyme MAT2A to maintain their epigenome. We hypothesized that cancer stem cells (CSCs) rely on SAM biosynthesis and that the combination of methionine depletion and MAT2A inhibition would eradicate CSCs.
Human triple (ER/PR/HER2)-negative breast carcinoma (TNBC) cell lines were cultured as CSC-enriched mammospheres in control or methionine-free media. MAT2A was inhibited with siRNAs or cycloleucine. The effects of methionine restriction and/or MAT2A inhibition on the formation of mammospheres, the expression of CSC markers (CD44hi/C24low), MAT2A and CSC transcriptional regulators, apoptosis induction and histone modifications were determined. A murine model of metastatic TNBC was utilized to evaluate the effects of dietary methionine restriction, MAT2A inhibition and the combination.
Methionine restriction inhibited mammosphere formation and reduced the CD44hi/C24low CSC population; these effects were partly rescued by SAM. Methionine depletion induced MAT2A expression (mRNA and protein) and sensitized CSCs to inhibition of MAT2A (siRNAs or cycloleucine). Cycloleucine enhanced the effects of methionine depletion on H3K4me3 demethylation and suppression of Sox9 expression. Dietary methionine restriction induced MAT2A expression in mammary tumors, and the combination of methionine restriction and cycloleucine was more effective than either alone at suppressing primary and lung metastatic tumor burden in a murine TNBC model.
Our findings point to SAM biosynthesis as a unique metabolic vulnerability of CSCs that can be targeted by combining methionine depletion with MAT2A inhibition to eradicate drug-resistant CSCs.
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We are indebted to members of the Cryns lab for their critical reading of the manuscript.
This work was supported by Grants from the Breast Cancer Research Foundation (VLC), V Foundation for Cancer Research (VLC), the Sidney Kimmel Foundation for Cancer Research (PWL), Wisconsin Partnership Program (VLC), National Institutes of Health grant P41GM108538 (JJC), University of Wisconsin Comprehensive Cancer Center Pilot Award (VLC and PWL) and P30CA14520 core facility support. We also acknowledge financial support from the Morgridge Institute for Research Metabolism Theme.
Conflict of interest
JJC is a consultant for Thermo Fisher Scientific. The other authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.
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Strekalova, E., Malin, D., Weisenhorn, E.M.M. et al. S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability of cancer stem cells. Breast Cancer Res Treat 175, 39–50 (2019). https://doi.org/10.1007/s10549-019-05146-7
- Breast cancer
- Cancer stem cell