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Endocrine Abstracts (2018) 59 OC6.6 | DOI: 10.1530/endoabs.59.OC6.6

SFEBES2018 Oral Communications Neuroendocrinology and Reproduction (6 abstracts)

An epigenetic modifier reduces proliferation in pituitary cells and suppresses calcium-sensing receptor signalling

Kate E Lines 1 , Anna K Gluck 1 , Chas Bountra 2 , Rajesh V Thakker 1 & Caroline M Gorvin 3,


1OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK; 2Structural Genomics Consortium, University of Oxford, Oxford, UK; 3Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK; 4Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK.


JQ1 is a bromodomain inhibitor that specifically targets the BET protein family (comprising Brd2, Brd3, Brd4 and BrdT), which promote the transcription of genes by binding acetylated histone residues and recruiting transcriptional machinery. JQ1 has been shown to have efficacy in the treatment of neuroendocrine tumours, however the genes regulated by the BET family in endocrine tissues, particularly in the pituitary, have not been elucidated. We therefore performed RNA-Seq analysis on the mouse corticotrophinoma pituitary cell-line AtT20 following treatment with JQ1, or the JQ1 negative stereoisomer JQ1-. This identified the calcium-sensing receptor (CaSR) gene, Casr, and six genes within its signalling pathway, as significantly downregulated, which we confirmed by quantitative PCR. CaSR is a G-protein-coupled receptor that detects extracellular calcium (Ca2+e) and elicits calcitropic (calcium homeostasis) and non-calcitropic effects through multiple G-protein pathways. Within normal pituitary cells, CaSR helps regulate anterior pituitary hormone secretion. However, in AtT20 cells CaSR activates a tumour-specific cAMP pathway that promotes ACTH and PTHrP secretion. Based on these results we hypothesised that the Casr promoter must harbour binding sites for BET proteins, and that JQ1 treatment should suppress CaSR signalling. Using chromatin Immunoprecipitation (ChIP)-sequencing we demonstrated that the BET protein Brd3 binds to the promoter of 5 of the genes identified as downregulated by RNA-sDefault (CaSR, Plch1, Plce1, Prkcg and Creb3I2). To determine if JQ1 treatment altered CaSR-mediated signalling we measured Ca2+e-induced intracellular calcium (Ca2+i) mobilisation using a fluo-4 calcium assay, and cAMP signalling using a CRE luciferase reporter assay. We demonstrate that JQ1 treatment significantly decreased both Ca2+i and cAMP signalling, compared to DMSO or JQ1- treated cells. Thus, aberrant CaSR signalling in pituitary tumour cells can be regulated by epigenetic modifiers, and the CaSR pathway represents a novel target in pituitary tumorigenesis.

Volume 59

Society for Endocrinology BES 2018

Glasgow, UK
19 Nov 2018 - 21 Nov 2018

Society for Endocrinology 

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