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

doi:10.1016/j.bbrc.2009.12.072

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 journal › Article › peer-review

21 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	1396-1399
Number of pages	4
Journal	Biochemical and Biophysical Research Communications
Volume	391
Issue number	3
DOIs	https://doi.org/10.1016/j.bbrc.2009.12.072
Publication status	Published - Jan 15 2010
Externally published	Yes

Keywords

Acetylation
Histone deacetylase
Histone deacetylase inhibitor
Methotrexate

ASJC Scopus subject areas

Molecular Biology
Biophysics
Biochemistry
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbrc.2009.12.072

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title = "Inhibition of histone deacetylase activity is a novel function of the antifolate drug methotrexate",

abstract = "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.",

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AU - Lin, Jung Hsin

AU - Huang, Wen Yu

AU - Lin, Yi Chu

AU - Yeh, Shu Hao

AU - Chen, Ching Chow

PY - 2010/1/15

Y1 - 2010/1/15

N2 - 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.

AB - 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.

KW - Acetylation

KW - Histone deacetylase

KW - Histone deacetylase inhibitor

KW - Methotrexate

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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