Epidrug-mediated reversal of epigenetic changes associated with pituitary adenomas

Doctoral thesis English OPEN
Yacqub-Usman, Kiren (2013)
  • Subject: RM

The genesis and outgrowth of pituitary adenomas is consequent to the combined contributions of genetic and epigenetic aberrations. Although the relative contribution of each is not known it is likely that particular aberration may be common or particular to an adenoma subtype(s). The impact of subtype specific changes presents significant challenges for clinical management options. In this thesis the potential impact of epigenetic aberrations, that target the Dopamine D2 Receptor (D2R) and the cytokine, Bone Morphogenic Protein 4 (BMP-4) were investigated. In these cases their expression patterns are frequently comprised in a subtype-specific context. This thesis reports that in pituitary cell lines, reduced expression of D2R and that of BMP4 are associated with CpG island methylation and histone modifications indicative of gene silencing. In these cases, incubation of cells with epidrugs, designed to reverse epigenetic silencing, restores their expression.
  • References (5)

    1. Haneen Al-Azzawi*, Kiren Yacqub-Usman*, Alan Richardson, Leo Hofland, Richard N Clayton, William E Farrell. Reversal of Endogenous Dopamine Receptor Silencing in Pituitary Cells Augments Receptor-Mediated Apoptosis. Endocrinology (2011) 152: (2) 364-373.

    2. Kiren Yacqub-Usman, Alan Richardson, Cuong V. Duong, Richard N Clayton, William E Farrell. The pituitary tumour epigenome: aberrations and prospects for targeted therapy. Nature Reviews Endocrinology (2012) 8:(8) 486-94

    3. Kiren Yacqub-Usman, Cuong V. Duong, Richard N Clayton, William E Farrell. Epigenomic Silencing of the BMP-4 Gene in Pituitary Adenomas: A Potential Target for EpidrugInduced re-expression. Endocrinology (2012) 153:(8) 3603-12

    4. Cuong V. Duong, Richard D Emes, Frank Wessely, Kiren Yacqub-Usman, Richard N Clayton, William E Farrell. Quantitative, genome-wide analysis of the DNA methylome in sporadic pituitary adenomas. Endocrine Related Cancer (2012) 19:1-12

    5. Kiren Yacqub-Usman, Cuong V. Duong, Richard N Clayton, William E Farrell. Preincubation of Pituitary Tumour Cells with the Epidrugs Zebularine and Trichostatin A are Permissive for Retinoic Acid Augmented Expression of the BMP-4 and D2R genes. Endocrinology (2013) 154:(5) 1711-21

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