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The pituitary tumour epigenome: aberrations and prospects for targeted therapy

Nature Reviews Endocrinology volume 8, pages 486–494 (2012)Cite this article

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Abstract

Global and gene-specific changes in the epigenome are hallmarks of most tumour types, including those of pituitary origin. In contrast to genetic mutations, epigenetic changes (aberrant DNA methylation and histone modifications) are potentially reversible. Drugs that specifically target or inhibit DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) can be used to restore the expression of epigenetically silenced genes. These drugs can potentially increase the sensitivity of tumour cells to conventional treatment modalities, such as chemotherapy and radiotherapy. Drug-induced reversal of transcriptional silencing can also be used to restore dopamine-D2-receptor-negative, hormone-refractory tumours to their previous receptor-positive, hormone-responsive status. Synergy between HDAC and DNMT inhibitors makes these pharmacological agents more therapeutically effective when administered in combination than when used alone. Studies in pituitary tumour cell lines show that drug-induced re-expression of the epigenetically silenced dopamine D2 receptor leads to an increase in apoptosis mediated by a receptor agonist. Collectively, the use of drugs to directly or indirectly reverse gene-specific epigenetic changes, in combination with conventional therapeutic interventions, has potential for the clinical management of multiple tumour types—including those of pituitary origin. Furthermore, these drugs can be used to identify epigenetically regulated genes that could be novel, tumour-specific therapeutic targets.

Key Points

  • Global and gene-specific changes to the epigenome are hallmarks of most cancer types, including pituitary tumours

  • Changes to the epigenome, such as aberrant DNA methylation and histone modifications, frequently lead to inappropriate expression or silencing of genes

  • Unlike genetic mutations, epigenetic changes are potentially reversible

  • Drug-mediated reversal of epigenetic transcriptional silencing can increase tumour sensitivity to conventional treatments

  • Proof-of-principle studies show that epigenome-targeting drugs can induce re-expression of the epigenetically silenced dopamine D2 receptor in pituitary tumour cells, and augment apoptosis through a receptor-agonist-mediated pathway

  • Novel strategies for either direct or indirect reversal of aberrant epigenetic changes might provide new therapeutic options for the clinical management of pituitary tumours

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Figure 1: Epigenetic modifications associated with transcriptionally active and transcriptionally silent genes.
Figure 2: Interdependence of DNA methylation and histone modifications.
Figure 3: Expression of dopamine D2 receptor mRNA following treatment with zebularine or trichostatin A, alone or in combination.
Figure 4: Analysis of the D2DR promoter region by chromatin immunoprecipitation.

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  1. Human Disease and Genomics Group, Institute of Science and Technology in Medicine, School of Medicine, Keele University, Stoke-on-Trent, ST4 7QB, Staffordshire, UK

    Kiren Yacqub-Usman, Alan Richardson, Cuong V. Duong, Richard N. Clayton & William E. Farrell

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K. Yacqub-Usman, A. Richardson, C. V. Duong and W. E. Farrell researched data for the Review and all authors made substantial contributions to discussion of content. W. E. Farrell wrote and edited the article. A. Richardson and R. N. Clayton also edited the manuscript before submission.

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Correspondence to William E. Farrell.

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Yacqub-Usman, K., Richardson, A., Duong, C. et al. The pituitary tumour epigenome: aberrations and prospects for targeted therapy. Nat Rev Endocrinol 8, 486–494 (2012). https://doi.org/10.1038/nrendo.2012.54

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