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FEBS Open Bio. 2014 Oct 16;4:987-95. doi: 10.1016/j.fob.2014.10.007. eCollection 2014.

Anticancer drug mithramycin interacts with core histones: An additional mode of action of the DNA groove binder.

Author information

1
Biophysics & Structural Genomics Division, Saha Institute of Nuclear Physics, Block-AF, Sector-1, Bidhan Nagar, Kolkata 700064, West Bengal, India.
2
Bionivid Technology Pvt Ltd, Kasturi Nagar, Bangalore 560043, India.
3
Division of Molecular Medicine, Centre for Translational Animal Research, Bose Institute, P-1/12 C.I.T. Scheme VIIM, Kolkata 700054, West Bengal, India.
4
Structural Biology and Bioinformatics, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India.

Abstract

Mithramycin (MTR) is a clinically approved DNA-binding antitumor antibiotic currently in Phase 2 clinical trials at National Institutes of Health for treatment of osteosarcoma. In view of the resurgence in the studies of this generic antibiotic as a human medicine, we have examined the binding properties of MTR with the integral component of chromatin - histone proteins - as a part of our broad objective to classify DNA-binding molecules in terms of their ability to bind chromosomal DNA alone (single binding mode) or both histones and chromosomal DNA (dual binding mode). The present report shows that besides DNA, MTR also binds to core histones present in chromatin and thus possesses the property of dual binding in the chromatin context. In contrast to the MTR-DNA interaction, association of MTR with histones does not require obligatory presence of bivalent metal ion like Mg(2+). As a consequence of its ability to interact with core histones, MTR inhibits histone H3 acetylation at lysine 18, an important signature of active chromatin, in vitro and ex vivo. Reanalysis of microarray data of Ewing sarcoma cell lines shows that upon MTR treatment there is a significant down regulation of genes, possibly implicating a repression of H3K18Ac-enriched genes apart from DNA-binding transcription factors. Association of MTR with core histones and its ability to alter post-translational modification of histone H3 clearly indicates an additional mode of action of this anticancer drug that could be implicated in novel therapeutic strategies.

KEYWORDS:

BAC, benzalkonium chloride; BSA, bovine serum albumin; CBP, CREB-binding protein; CD, circular dichroism; Core histones; Dual binding mode; EM, electron microscopy; EWS-FLI1, transcription factor with a DNA binding domain FLI1 and a transcription enhancer domain EWS; Epigenetic modulator; FACS, fluorescence activated cell sorting; H3K18 acetylation; H3K18Ac, histone H3 lysine 18 acetylation; HAT, histone acetyltransferase; HD, Huntington’s disease; ITC, isothermal titration calorimetry; M2+, bivalent metal ion such as Mg2+; MTR, mithramycin; MTT, 3-(4-5 dimethylthiazol-2-yl) 2-5diphenyl-tetrazolium bromide; Mithramycin; NIH, National Institutes of Health; PBS, phosphate-buffered saline; PTM, post-translational modification; SGR, sanguinarine; TBST, Tris-buffered saline Tween-20; TCA, trichloroacetic acid

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