Epigenetic pathway inhibitors represent potential drugs for treating pancreatic and bronchial neuroendocrine tumors

摘要: Cancer is associated with alterations in epigenetic mechanisms such as histone modifications and methylation of DNA, inhibitors targeting represent a novel class anti-cancer drugs. Neuroendocrine tumors (NETs) the pancreas (PNETs) bronchus (BNETs), which may have 5-year survivals 40% PNETs ~35% BNETs mutations multiple endocrine neoplasia type 1 (MEN1) gene, encodes menin that modifies histones by interacting methyltransferases. We assessed 9 pathways, for their effects on proliferation, CellTiter Blue assay, apoptosis, CaspaseGlo using PNET 2 BNET cell lines. Two inhibitors, referred to (+)-JQ1 (JQ1) PFI-1, bromo extra terminal (BET) protein family bind acetylated residues, were most effective decreasing proliferation (by 40-85%, P<0.001) increasing apoptosis 2-3.6 fold, all 3 NET The anti-proliferative JQ1 PFI-1 remained present at least 48 hours after removal compound. JQ1, but not had cycle effects, propidium iodide staining flow cytometry, resulting increased decreased proportions cells G1, S G2 phases, respectively. RNA Sequencing analysis revealed these 2B expression, likely mediated through altered activity bromodomain-containing (Brd) proteins. Assessment vivo, pancreatic beta cell-specific conditional Men1 knockout mouse model develops PNETs, significantly reduced ~50%, P<0.0005), bromodeoxyuridine incorporation, ~3 deoxynucleotidyl transferase dUTP nick end labelling, PNETs. Thus, our studies demonstrate BET provide new treatments NETs.