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Breast Cancer Research and Treatment

, Volume 175, Issue 1, pp 39–50 | Cite as

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

  • Elena Strekalova
  • Dmitry Malin
  • Erin M. M. Weisenhorn
  • Jason D. Russell
  • Dominik Hoelper
  • Aayushi Jain
  • Joshua J. Coon
  • Peter W. Lewis
  • Vincent L. CrynsEmail author
Preclinical study

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.

Keywords

Methionine Breast cancer S-adenosylmethionine Nutrition Cancer stem cell Therapeutics 

Notes

Acknowledgements

We are indebted to members of the Cryns lab for their critical reading of the manuscript.

Funding

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.

Compliance with ethical standards

Conflict of interest

JJC is a consultant for Thermo Fisher Scientific. The other authors declare that they have no conflict of interest.

Ethical approval

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.

Supplementary material

10549_2019_5146_MOESM1_ESM.pdf (496 kb)
Supplementary material 1 (PDF 496 KB)

References

  1. 1.
    Shiraki N, Shiraki Y, Tsuyama T, Obata F, Miura M, Nagae G et al (2014) Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells. Cell Metab 19:780–794CrossRefGoogle Scholar
  2. 2.
    Chandrasekaran S, Zhang J, Sun Z, Zhang L, Ross CA, Huang YC et al (2017) Comprehensive mapping of pluripotent stem cell metabolism using dynamic genome-scale network modeling. Cell Rep 21:2965–2977CrossRefGoogle Scholar
  3. 3.
    Maldonado LY, Arsene D, Mato JM, Lu SC (2018) Methionine adenosyltransferases in cancers: mechanisms of dysregulation and implications for therapy. Exp Biol Med (Maywood) 243:107–117CrossRefGoogle Scholar
  4. 4.
    Locasale JW (2013) Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer 13:572–583CrossRefGoogle Scholar
  5. 5.
    Shyh-Chang N, Locasale JW, Lyssiotis CA, Zheng Y, Teo RY, Ratanasirintrawoot S et al (2013) Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science 339:222–226CrossRefGoogle Scholar
  6. 6.
    Ang YS, Tsai SY, Lee DF, Monk J, Su J, Ratnakumar K et al (2011) Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell 145:183–197CrossRefGoogle Scholar
  7. 7.
    Kreis W, Baker A, Ryan V, Bertasso A (1980) Effect of nutritional and enzymatic methionine deprivation upon human normal and malignant cells in tissue culture. Cancer Res 40:634–641Google Scholar
  8. 8.
    Guo H, Lishko VK, Herrera H, Groce A, Kubota T, Hoffman RM (1993) Therapeutic tumor-specific cell cycle block induced by methionine starvation in vivo. Cancer Res 53:5676–5679Google Scholar
  9. 9.
    Hoshiya Y, Guo H, Kubota T, Inada T, Asanuma F, Yamada Y et al (1995) Human tumors are methionine dependent in vivo. Anticancer Res 15:717–718Google Scholar
  10. 10.
    Lu S, Hoestje SM, Choo E, Epner DE (2003) Induction of caspase-dependent and -independent apoptosis in response to methionine restriction. Int J Oncol 22:415–420Google Scholar
  11. 11.
    Mecham JO, Rowitch D, Wallace CD, Stern PH, Hoffman RM (1983) The metabolic defect of methionine dependence occurs frequently in human tumor cell lines. Biochem Biophys Res Commun 117:429–434CrossRefGoogle Scholar
  12. 12.
    Halpern BC, Clark BR, Hardy DN, Halpern RM, Smith RA (1974) The effect of replacement of methionine by homocystine on survival of malignant and normal adult mammalian cells in culture. Proc Natl Acad Sci USA 71:1133–1136CrossRefGoogle Scholar
  13. 13.
    Durando X, Farges MC, Buc E, Abrial C, Petorin-Lesens C, Gillet B et al (2010) Dietary methionine restriction with FOLFOX regimen as first line therapy of metastatic colorectal cancer: a feasibility study. Oncology 78:205–209CrossRefGoogle Scholar
  14. 14.
    Epner DE, Morrow S, Wilcox M, Houghton JL (2002) Nutrient intake and nutritional indexes in adults with metastatic cancer on a phase I clinical trial of dietary methionine restriction. Nutr Cancer 42:158–166CrossRefGoogle Scholar
  15. 15.
    Thivat E, Durando X, Demidem A, Farges MC, Rapp M, Cellarier E et al (2007) A methionine-free diet associated with nitrosourea treatment down-regulates methylguanine-DNA methyl transferase activity in patients with metastatic cancer. Anticancer Res 27:2779–2783Google Scholar
  16. 16.
    Strekalova E, Malin D, Good DM, Cryns VL (2015) Methionine deprivation induces a targetable vulnerability in triple-negative breast cancer cells by enhancing TRAIL receptor-expression. Clin Cancer Res 21:2780–2791CrossRefGoogle Scholar
  17. 17.
    Shibue T, Weinberg RA (2017) EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14:611–629CrossRefGoogle Scholar
  18. 18.
    Martinez-Chantar ML, Latasa MU, Varela-Rey M, Lu SC, Garcia-Trevijano ER, Mato JM et al (2003) L-methionine availability regulates expression of the methionine adenosyltransferase 2A gene in human hepatocarcinoma cells: role of S-adenosylmethionine. J Biol Chem 278:19885–19890CrossRefGoogle Scholar
  19. 19.
    Malin D, Strekalova E, Petrovic V, Deal AM, Al Ahmad A, Adamo B et al (2014) αB-crystallin: a novel regulator of breast cancer metastasis to the brain. Clin Cancer Res 20:56–67CrossRefGoogle Scholar
  20. 20.
    Malin D, Strekalova E, Petrovic V, Rajanala H, Sharma B, Ugolkov A et al (2015) ERK-regulated αB-crystallin induction by matrix detachment inhibits anoikis and promotes lung metastasis in vivo. Oncogene 34:5626–5634CrossRefGoogle Scholar
  21. 21.
    Moyano JV, Evans JR, Chen F, Lu M, Werner ME, Yehiely F et al (2006) αB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer. J Clin Invest 116:261–270CrossRefGoogle Scholar
  22. 22.
    Lu C, Jain SU, Hoelper D, Bechet D, Molden RC, Ran L et al (2016) Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science 352:844–849CrossRefGoogle Scholar
  23. 23.
    Hoelper D, Huang H, Jain AY, Patel DJ, Lewis PW (2017) Structural and mechanistic insights into ATRX-dependent and -independent functions of the histone chaperone DAXX. Nat Commun 8:1193CrossRefGoogle Scholar
  24. 24.
    Malin D, Chen F, Schiller C, Koblinski J, Cryns VL (2011) Enhanced metastasis suppression by targeting TRAIL receptor 2 in a murine model of triple-negative breast cancer. Clin Cancer Res 17:5005–5015CrossRefGoogle Scholar
  25. 25.
    Sufrin JR, Coulter AW, Talalay P (1979) Structural and conformational analogues of L-methionine as inhibitors of the enzymatic synthesis of S-adenosyl-l-methionine. IV. Further mono-, bi- and tricyclic amino acids. Mol Pharmacol 15:661–677Google Scholar
  26. 26.
    Mentch SJ, Mehrmohamadi M, Huang L, Liu X, Gupta D, Mattocks D et al (2015) Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab 22:861–873CrossRefGoogle Scholar
  27. 27.
    Jeselsohn R, Cornwell M, Pun M, Buchwalter G, Nguyen M, Bango C et al (2017) Embryonic transcription factor SOX9 drives breast cancer endocrine resistance. Proc Natl Acad Sic USA 114:E4482–E4491CrossRefGoogle Scholar
  28. 28.
    Yu F, Li J, Chen H, Fu J, Ray S, Huang S et al (2011) Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion. Oncogene 30:2161–2172CrossRefGoogle Scholar
  29. 29.
    Greco CM, Powell HC, Garrett RS, Lampert PW (1980) Cycloleucine encephalopathy. Neuropathol Appl Neurobiol 6:349–360CrossRefGoogle Scholar
  30. 30.
    Guarino AM, Rozencweig M, Kline I, Penta JS, Venditti JM, Lloyd HH et al (1979) Adequacies and inadequacies in assessing murine toxicity data with antineoplastic agents. Cancer Res 39:2204–2210Google Scholar
  31. 31.
    Savlov ED, MacIntyre JM, Knight E, Wolter J (1981) Comparison of doxorubicin with cycloleucine in the treatment of sarcomas. Cancer Treat Rep 65:21–27Google Scholar
  32. 32.
    Quinlan CL, Kaiser SE, Bolanos B, Nowlin D, Grantner R, Karlicek-Bryant S et al (2017) Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A. Nat Chem Biol 13:785–792CrossRefGoogle Scholar
  33. 33.
    Stone KP, Wanders D, Orgeron M, Cortez CC, Gettys TW (2014) Mechanisms of increased in vivo insulin sensitivity by dietary methionine restriction in mice. Diabetes 63:3721–3733CrossRefGoogle Scholar
  34. 34.
    Yu D, Yang SE, Miller BR, Wisinski JA, Sherman DS, Brinkman JA et al (2018) Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms. FASEB J 32(6):3471–3482CrossRefGoogle Scholar
  35. 35.
    Liu Q, Liu L, Zhao Y, Zhang J, Wang D, Chen J et al (2011) Hypoxia induces genomic DNA demethylation through the activation of HIF-1alpha and transcriptional upregulation of MAT2A in hepatoma cells. Mol Cancer Ther 10:1113–1123CrossRefGoogle Scholar
  36. 36.
    Yang H, Li TW, Peng J, Mato JM, Lu SC (2011) Insulin-like growth factor 1 activates methionine adenosyltransferase 2A transcription by multiple pathways in human colon cancer cells. Biochem J 436:507–516CrossRefGoogle Scholar
  37. 37.
    Phuong NT, Kim SK, Im JH, Yang JW, Choi MC, Lim SC et al (2016) Induction of methionine adenosyltransferase 2A in tamoxifen-resistant breast cancer cells. Oncotarget 7:13902–13916CrossRefGoogle Scholar
  38. 38.
    Liu Q, Wu K, Zhu Y, He Y, Wu J, Liu Z (2007) Silencing MAT2A gene by RNA interference inhibited cell growth and induced apoptosis in human hepatoma cells. Hepatol Res 37:376–388CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Elena Strekalova
    • 1
  • Dmitry Malin
    • 1
  • Erin M. M. Weisenhorn
    • 2
  • Jason D. Russell
    • 3
    • 4
  • Dominik Hoelper
    • 2
  • Aayushi Jain
    • 2
  • Joshua J. Coon
    • 2
    • 3
    • 4
    • 5
  • Peter W. Lewis
    • 2
  • Vincent L. Cryns
    • 1
    • 6
    Email author
  1. 1.Department of Medicine, University of Wisconsin Carbone Cancer CenterUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  2. 2.Department of Biomolecular Chemistry, University of Wisconsin Carbone Cancer CenterUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  3. 3.Morgridge Institute for ResearchMadisonUSA
  4. 4.Genome Center of WisconsinUniversity of Wisconsin-MadisonMadisonUSA
  5. 5.Department of ChemistryUniversity of Wisconsin-MadisonMadisonUSA
  6. 6.Department of Medicine, University of Wisconsin Carbone Cancer CenterUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA

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