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Mechanisms of Disease: methyl-binding domain proteins as potential therapeutic targets in cancer

Nature Clinical Practice Oncology volume 4, pages 305–315 (2007)Cite this article

Abstract

The methyl-CpG-binding domain (MBD) proteins 'read' and interpret the methylation moieties on DNA, and thus are critical mediators of many epigenetic processes. Currently, the MBD family comprises five members; MBD1, MBD2, MBD3, MBD4 and MeCP2. Although not a 'classical' MBD protein, Kaiso also mediates transcriptional repression by using zinc finger domains to bind its targets. Since DNA hypermethylation is a well-recognized mechanism underlying gene silencing events in both tumorigenesis and drug resistance, it is likely that the MBD proteins may be important modulators of tumorigenesis. We review the recent work addressing this possibility, and discuss several of the MBD proteins as potentially excellent novel therapeutic targets.

Key Points

  • Modulation of DNA methylation patterns and the proteins that interpret those patterns modifies the neoplastic process

  • Reduction in levels of DNMT1 reduces tumorigenesis in some tissues, but exacerbates it in other tissues

  • MBD2 deficiency has been shown to suppress intestinal neoplasia in animal models, with apparently little protumorigenic role in other tissues, so identifying it as a promising new therapeutic target

  • Kaiso deficiency has been shown to suppress intestinal neoplasia, identifying it as a promising therapeutic target

  • MBD4 deficiency has multiple effects upon tumorigenesis, but its primary consequence is an increase in mutation rates through failed DNA repair of spontaneous deamination events

  • Although implicated in the neoplastic process, the precise roles of MBD1, MBD3 and MeCP2 remain to be established

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Figure 1: Schematic structure of the major MBD family members
Figure 2: Simplified diagram showing the modes of action of DNMT1, MBD2, MBD3, Kaiso, MBD4 and MeCP2
Figure 3: The MBD proteins and neoplasia

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Authors and Affiliations

  1. OJ Sansom is Group Leader at The Beatson Institute, Garscube Estate, Glasgow,

    Owen J Sansom

  2. K Maddison is a Postdoctoral Fellow, and AR Clarke is Professor of Genetics and Joint Head of Research, at the Cardiff School of Biosciences, Cardiff University, Cardiff, UK.,

    Kathryn Maddison & Alan R Clarke

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Correspondence to Alan R Clarke.

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Sansom, O., Maddison, K. & Clarke, A. Mechanisms of Disease: methyl-binding domain proteins as potential therapeutic targets in cancer. Nat Rev Clin Oncol 4, 305–315 (2007). https://doi.org/10.1038/ncponc0812

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