Inhibition of histone deacetylase activity is a novel function of the antifolate drug methotrexate.
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.
Yang
Pei-Ming
PM
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 10018, Taiwan.
Lin
Jung-Hsin
JH
Huang
Wen-Yu
WY
Lin
Yi-Chu
YC
Yeh
Shu-Hao
SH
Chen
Ching-Chow
CC
D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008727:Methotrexate / Q000737:chemistry / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D008727:Methotrexate