PMID- 28504695
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240306
IS  - 2157-9024 (Print)
IS  - 2157-9024 (Electronic)
IS  - 2157-9024 (Linking)
VI  - 6
IP  - 5
DP  - 2017 May 15
TI  - Epigenetic pathway inhibitors represent potential drugs for treating pancreatic 
      and bronchial neuroendocrine tumors.
PG  - e332
LID - 10.1038/oncsis.2017.30 [doi]
AB  - Cancer is associated with alterations in epigenetic mechanisms such as histone 
      modifications and methylation of DNA, and inhibitors targeting epigenetic 
      mechanisms represent a novel class of anti-cancer drugs. Neuroendocrine tumors 
      (NETs) of the pancreas (PNETs) and bronchus (BNETs), which may have 5-year 
      survivals of <50% and as low as 5%, respectively, represent targets for such 
      drugs, as >40% of PNETs and ~35% of BNETs have mutations of the multiple 
      endocrine neoplasia type 1 (MEN1) gene, which encodes menin that modifies 
      histones by interacting with histone methyltransferases. We assessed 9 inhibitors 
      of epigenetic pathways, for their effects on proliferation, by CellTiter Blue 
      assay, and apoptosis, by CaspaseGlo assay, using 1 PNET and 2 BNET cell lines. 
      Two inhibitors, referred to as (+)-JQ1 (JQ1) and PFI-1, targeting the bromo and 
      extra terminal (BET) protein family which bind acetylated histone residues, were 
      most effective in decreasing proliferation (by 40-85%, P<0.001) and increasing 
      apoptosis (by 2-3.6 fold, P<0.001) in all 3 NET cell lines. The 
      anti-proliferative effects of JQ1 and PFI-1 remained present for at least 48 
      hours after removal of the compound. JQ1, but not PFI-1, had cell cycle effects, 
      assessed by propidium iodide staining and flow cytometry, resulting in increased 
      and decreased proportions of NET cells in G1, and S and G2 phases, respectively. 
      RNA Sequencing analysis revealed that these JQ1 effects were associated with 
      increased histone 2B expression, and likely mediated through altered activity of 
      bromodomain-containing (Brd) proteins. Assessment of JQ1 in vivo, using a 
      pancreatic beta cell-specific conditional Men1 knockout mouse model that develops 
      PNETs, revealed that JQ1 significantly reduced proliferation (by ~50%, P<0.0005), 
      assessed by bromodeoxyuridine incorporation, and increased apoptosis (by ~3 fold, 
      P<0.0005), assessed by terminal deoxynucleotidyl transferase dUTP nick end 
      labelling, of PNETs. Thus, our studies demonstrate that BET protein inhibitors 
      may provide new treatments for NETs.
FAU - Lines, K E
AU  - Lines KE
AD  - Academic Endocrine Unit, OCDEM, University of Oxford, Churchill Hospital, 
      Headington, Oxford, UK.
FAU - Stevenson, M
AU  - Stevenson M
AD  - Academic Endocrine Unit, OCDEM, University of Oxford, Churchill Hospital, 
      Headington, Oxford, UK.
FAU - Filippakopoulos, P
AU  - Filippakopoulos P
AD  - Structural Genomics Consortium, University of Oxford, Old Road Campus, 
      Headington, Oxford, UK.
FAU - Muller, S
AU  - Muller S
AD  - Structural Genomics Consortium, University of Oxford, Old Road Campus, 
      Headington, Oxford, UK.
FAU - Lockstone, H E
AU  - Lockstone HE
AD  - Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, University of 
      Oxford, Roosevelt Drive, Oxford, UK.
FAU - Wright, B
AU  - Wright B
AD  - Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, University of 
      Oxford, Roosevelt Drive, Oxford, UK.
FAU - Grozinsky-Glasberg, S
AU  - Grozinsky-Glasberg S
AD  - Neuroendocrine Tumor Unit, Endocrinology &Metabolism Service, Department of 
      Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
FAU - Grossman, A B
AU  - Grossman AB
AD  - Academic Endocrine Unit, OCDEM, University of Oxford, Churchill Hospital, 
      Headington, Oxford, UK.
FAU - Knapp, S
AU  - Knapp S
AD  - Structural Genomics Consortium, University of Oxford, Old Road Campus, 
      Headington, Oxford, UK.
AD  - Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University and 
      Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Strasse 9, Frankfurt 
      am Main, Jerusalem, Germany.
FAU - Buck, D
AU  - Buck D
AD  - Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, University of 
      Oxford, Roosevelt Drive, Oxford, UK.
FAU - Bountra, C
AU  - Bountra C
AD  - Structural Genomics Consortium, University of Oxford, Old Road Campus, 
      Headington, Oxford, UK.
FAU - Thakker, R V
AU  - Thakker RV
AD  - Academic Endocrine Unit, OCDEM, University of Oxford, Churchill Hospital, 
      Headington, Oxford, UK.
LA  - eng
GR  - G1000467/MRC_/Medical Research Council/United Kingdom
GR  - G9825289/MRC_/Medical Research Council/United Kingdom
GR  - MR/N010051/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
DEP - 20170515
PL  - United States
TA  - Oncogenesis
JT  - Oncogenesis
JID - 101580004
PMC - PMC5523063
COIS- The authors declare no conflict of interest.
EDAT- 2017/05/16 06:00
MHDA- 2017/05/16 06:01
PMCR- 2017/05/01
CRDT- 2017/05/16 06:00
PHST- 2016/10/20 00:00 [received]
PHST- 2017/03/24 00:00 [revised]
PHST- 2017/03/28 00:00 [accepted]
PHST- 2017/05/16 06:00 [entrez]
PHST- 2017/05/16 06:00 [pubmed]
PHST- 2017/05/16 06:01 [medline]
PHST- 2017/05/01 00:00 [pmc-release]
AID - oncsis201730 [pii]
AID - 10.1038/oncsis.2017.30 [doi]
PST - epublish
SO  - Oncogenesis. 2017 May 15;6(5):e332. doi: 10.1038/oncsis.2017.30.