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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2019

01-05-2019 | Preclinical study

S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability of cancer stem cells

Authors: Elena Strekalova, Dmitry Malin, Erin M. M. Weisenhorn, Jason D. Russell, Dominik Hoelper, Aayushi Jain, Joshua J. Coon, Peter W. Lewis, Vincent L. Cryns

Published in: Breast Cancer Research and Treatment | Issue 1/2019

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.
Appendix
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Metadata
Title
S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability of cancer stem cells
Authors
Elena Strekalova
Dmitry Malin
Erin M. M. Weisenhorn
Jason D. Russell
Dominik Hoelper
Aayushi Jain
Joshua J. Coon
Peter W. Lewis
Vincent L. Cryns
Publication date
01-05-2019
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2019
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-019-05146-7

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