Methotrexate as an HDAC inhibitor

[Kofi]

How much of methotrexate's benefits in cancer and autoimmunity are due
to HDAC inhibition and how much due to dihydrofolate reductase
inhibition?

I wonder if EGCG also displays this same activity.

Biochem Biophys Res Commun. 2009 Dec 21
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Inhibition of histone deacetylase activity is a novel function of the
antifolate drug methotrexate.
Yang PM, Lin JH, Huang WY, Lin YC, Yeh SH, Chen CC.
Department of Pharmacology, College of Medicine, National Taiwan
University, Taipei 10018, Taiwan.

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. Copyright (c) 2009 Elsevier Inc. All rights reserved.

PMID: 20026300