Effects of epigenetic pathway inhibitors on corticotroph tumour AtT20 cells

  • K E Lines
    1OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
  • P Filippakopoulos
    2Structural Genomics Consortium, University of Oxford, Oxford, UK
  • M Stevenson
    1OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
  • S Müller
    3Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Frankfurt, Germany
  • H E Lockstone
    4Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  • B Wright
    4Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  • S Knapp
    3Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Frankfurt, Germany
  • D Buck
    4Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  • C Bountra
    2Structural Genomics Consortium, University of Oxford, Oxford, UK
  • R V Thakker
    1OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK

抄録

<jats:p>Medical treatments for corticotrophinomas are limited, and we therefore investigated the effects of epigenetic modulators, a new class of anti-tumour drugs, on the murine adrenocorticotropic hormone (ACTH)-secreting corticotrophinoma cell line AtT20. We found that AtT20 cells express members of the bromo and extra-terminal (BET) protein family, which bind acetylated histones, and therefore, studied the anti-proliferative and pro-apoptotic effects of two BET inhibitors, referred to as (+)-JQ1 (JQ1) and PFI-1, using CellTiter Blue and Caspase Glo assays, respectively. JQ1 and PFI-1 significantly decreased proliferation by 95% (<jats:italic>P</jats:italic> < 0.0005) and 43% (<jats:italic>P</jats:italic> < 0.0005), respectively, but only JQ1 significantly increased apoptosis by >50-fold (<jats:italic>P</jats:italic> < 0.0005), when compared to untreated control cells. The anti-proliferative effects of JQ1 and PFI-1 remained for 96 h after removal of the respective compound. JQ1, but not PFI-1, affected the cell cycle, as assessed by propidium iodide staining and flow cytometry, and resulted in a higher number of AtT20 cells in the sub G1 phase. RNA-sequence analysis, which was confirmed by qRT-PCR and Western blot analyses, revealed that JQ1 treatment significantly altered expression of genes involved in apoptosis, such as NFκB, and the somatostatin receptor 2 (SSTR2) anti-proliferative signalling pathway, including SSTR2. JQ1 treatment also significantly reduced transcription and protein expression of the ACTH precursor pro-opiomelanocortin (POMC) and ACTH secretion by AtT20 cells. Thus, JQ1 treatment has anti-proliferative and pro-apoptotic effects on AtT20 cells and reduces ACTH secretion, thereby indicating that BET inhibition may provide a novel approach for treatment of corticotrophinomas.</jats:p>

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