Metformin Decreases 2-HG Production through the MYC-PHGDH Pathway in Suppressing Breast Cancer Cell Proliferation

Sehyun Oh, Youngup Cho, Minsun Chang, Sunghyouk Park, Hyuk Nam Kwon

Research output: Contribution to journalArticleScientificpeer-review

Abstract

The biguanide drug metformin has been widely used for the treatment of type 2 diabetes, and there is evidence supporting the anticancer effect of metformin despite some controversy. Here, we report the growth inhibitory activity of metformin in the breast cancer (MCF-7) cells, both in vitro and in vivo, and the associated metabolic changes. In particular, a decrease in a well-known oncometabolite 2-hydroxyglutarate (2-HG) was discovered by a metabolomics approach. The decrease in 2-HG by metformin was accompanied by the reduction in histone methylation, consistent with the known tumorigenic mechanism of 2-HG. The relevance of 2-HG inhibition in breast cancer was also supported by a higher level of 2-HG in human breast cancer tissues. Genetic knockdown of PHGDH identified the PHGDH pathway as the producer of 2-HG in the MCF-7 cells that do not carry isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) mutations, the conventional producer of 2-HG. We also showed that metformin's inhibitory effect on the PHGDH-2HG axis may occur through the regulation of the AMPK-MYC pathway. Overall, our results provide an explanation for the coherent pathway from complex I inhibition to epigenetic changes for metformin's anticancer effect.
Original languageEnglish
Article number480
JournalMetabolites
Volume11
Issue number8
Number of pages15
ISSN2218-1989
DOIs
Publication statusPublished - Jul 2021
MoE publication typeA1 Journal article-refereed

Fields of Science

  • metformin
  • metabolomics
  • 2-HG
  • PHGDH
  • anticancer effect
  • ONCOMETABOLITE 2-HYDROXYGLUTARATE
  • IDH2 MUTATIONS
  • INHIBITOR
  • ACCUMULATION
  • CONTRIBUTES
  • PERSPECTIVE
  • HOMEOSTASIS
  • METABOLISM
  • BIGUANIDES
  • PREVENTION
  • 3122 Cancers
  • 3111 Biomedicine

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