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Endocrine Abstracts (2016) 44 P145 | DOI: 10.1530/endoabs.44.P145

1Academic Endocrine Unit, OCDEM, University of Oxford, Oxford, UK; 2Structural Genomics Consortium, University of Oxford, Oxford, UK.


Epigenetic modifications and chromatin remodelling have been demonstrated to play a key role in the development, and progression of multiple cancers, and compounds regulating these mechanisms represent a novel class of anti-cancer drugs. Menin, which is encoded by the MEN1 gene, whose mutations result in a syndrome characterised by pituitary, parathyroid and pancreatic islet tumours, binds histone modifying enzymes, including the histone methyltransferase MLL1. Furthermore, menin, together with the acetyl-lysine recognising bromo and extra terminal (BET) family protein, BRD4, has been shown to be an important mediator of transformation, e.g. in MLL-fusion leukemia, and blocking of binding of the BRD4 bromodomain to acetylated histones using the chemical inhibitor (+)-JQ1 (JQ1+) has been shown to have efficacy in several cancers, including Men1-associated pancreatic neuroendocrine tumours. We therefore hypothesised that JQ1+ may be effective in treating pituitary tumours, and we examined the efficacy of JQ1+ in vitro and in vivo using the mouse pituitary cell line, AtT20, and pituitary tumours developing in Men1L/L/RIP2-Cre mice, respectively. JQ1+1 μM treatment at 96 h significantly reduced AtT20 cell proliferation (assessed by CellTitre Blue assay) by 95% (P<0.0001), and significantly increased apoptosis (assessed by CaspaseGlo assay) by 53-fold (P<0.0001), compared to cells treated with an inactive stereoisomer control, JQ1−. To examine the in vivo efficacy of JQ1+, female Men1L/L/RIP2-Cre mice were injected twice weekly (i.p.) with either 50 mg/kg JQ1+ or JQ1−, or vehicle (n=4 mice per group), for one month and proliferation and apoptosis analysed in pituitary tumours using bromodeoxyuridine staining and TUNEL assay, respectively. JQ1+ significantly increased apoptosis when compared to JQ1− (3.4-fold increase, P<0.005) and vehicle (3.5-fold increase, P<0.005) treatments, but had no significant effects on pituitary tumour cell proliferation. Thus, BET protein inhibitors may represent novel compounds for the treatment of pituitary tumours.

Volume 44

Society for Endocrinology BES 2016

Brighton, UK
07 Nov 2016 - 09 Nov 2016

Society for Endocrinology 

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