Inhibition of histone deacetylase activity is a novel function of the antifolate drug methotrexate

Pei Ming Yang, Jung Hsin Lin, Wen Yu Huang, Yi Chu Lin, Shu Hao Yeh, Ching Chow Chen

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)


Methotrexate (MTX) is a dihydrofolate reductase (DHFR) inhibitor widely used for treating human cancers, and overexpression of histone deacetylase (HDAC) is usually found in tumors. HDAC inhibitors (HDACi) can reactivate tumor suppressor genes and serve as potential anti-cancer drugs. In this study, we found that MTX shared structural similarity with some HDACi and molecular modeling showed that MTX indeed docks into the active site of HDLP, a bacterial homologue of HDAC. Subsequent in vitro assay demonstrated MTX's inhibition on HDAC activity in human cancer cells. The global acetylation of histone H3 was also induced by MTX. Moreover, MTX inhibited immunoprecipitated HDAC1/2 activity but not their protein levels. This study provides evidence that MTX inhibits HDAC activity.

Original languageEnglish
Pages (from-to)1396-1399
Number of pages4
JournalBiochemical and Biophysical Research Communications
Issue number3
Publication statusPublished - Jan 15 2010
Externally publishedYes


  • Acetylation
  • Histone deacetylase
  • Histone deacetylase inhibitor
  • Methotrexate

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics
  • Biochemistry
  • Cell Biology


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