BRD4 as a therapeutic target for nonfunctioning and growth hormone pituitary adenoma.
Adenoma
/ drug therapy
Animals
Antineoplastic Agents
/ pharmacology
Cell Cycle Proteins
/ antagonists & inhibitors
Cell Line, Tumor
Growth Hormone-Secreting Pituitary Adenoma
/ drug therapy
Humans
Mice
Molecular Targeted Therapy
Pituitary Neoplasms
/ drug therapy
Rats
Transcription Factors
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
BRD4
GHPA
NFPA
ZBC-260
target
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
17 08 2020
17 08 2020
Historique:
pubmed:
5
4
2020
medline:
7
4
2021
entrez:
5
4
2020
Statut:
ppublish
Résumé
Nonfunctioning pituitary adenoma (NFPA) and growth hormone pituitary adenoma (GHPA) are major subtypes of pituitary adenomas (PAs). The primary treatment is surgical resection. However, radical excision remains challenging, and few effective medical therapies are available. It is urgent to find novel targets for the treatment. Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator that leads to aberrant transcriptional activation of oncogenes. Herein, we investigated the pathological role of BRD4 and evaluated the effectiveness of BRD4 inhibitors in the treatment of NFPA and GHPA. The expression of BRD4 was detected in NFPA, GHPA, and normal pituitary tissues. The efficacies of BRD4 inhibitors were evaluated in GH3 and MMQ cell lines, patient-derived tumor cells, and in vivo mouse xenograft models of PA. Standard western blots, real-time PCR, and flow cytometry experiments were performed to investigate the effect of BRD4 inhibitors on cell cycle progression, apoptosis, and the expression patterns of downstream genes. Immunohistochemistry studies demonstrated the overexpression of BRD4 in NFPA and GHPA. In vitro and in vivo studies showed that treatment with the BRD4 inhibitor ZBC-260 significantly inhibited the proliferation of PA cells. Further mechanistic studies revealed that ZBC-260 could downregulate the expression of c-Myc, B-cell lymphoma 2 (Bcl2), and related genes, which are vital factors in pituitary tumorigenesis. In this study, we determined the overexpression of BRD4 in NFPA and GHPA and assessed the effects of BRD4 inhibitors on PA cells in vitro and in vivo. Our findings suggest that BRD4 is a promising therapeutic target for NFPA and GHPA.
Sections du résumé
BACKGROUND
Nonfunctioning pituitary adenoma (NFPA) and growth hormone pituitary adenoma (GHPA) are major subtypes of pituitary adenomas (PAs). The primary treatment is surgical resection. However, radical excision remains challenging, and few effective medical therapies are available. It is urgent to find novel targets for the treatment. Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator that leads to aberrant transcriptional activation of oncogenes. Herein, we investigated the pathological role of BRD4 and evaluated the effectiveness of BRD4 inhibitors in the treatment of NFPA and GHPA.
METHODS
The expression of BRD4 was detected in NFPA, GHPA, and normal pituitary tissues. The efficacies of BRD4 inhibitors were evaluated in GH3 and MMQ cell lines, patient-derived tumor cells, and in vivo mouse xenograft models of PA. Standard western blots, real-time PCR, and flow cytometry experiments were performed to investigate the effect of BRD4 inhibitors on cell cycle progression, apoptosis, and the expression patterns of downstream genes.
RESULTS
Immunohistochemistry studies demonstrated the overexpression of BRD4 in NFPA and GHPA. In vitro and in vivo studies showed that treatment with the BRD4 inhibitor ZBC-260 significantly inhibited the proliferation of PA cells. Further mechanistic studies revealed that ZBC-260 could downregulate the expression of c-Myc, B-cell lymphoma 2 (Bcl2), and related genes, which are vital factors in pituitary tumorigenesis.
CONCLUSION
In this study, we determined the overexpression of BRD4 in NFPA and GHPA and assessed the effects of BRD4 inhibitors on PA cells in vitro and in vivo. Our findings suggest that BRD4 is a promising therapeutic target for NFPA and GHPA.
Identifiants
pubmed: 32246150
pii: 5815718
doi: 10.1093/neuonc/noaa084
pmc: PMC7594556
doi:
Substances chimiques
Antineoplastic Agents
0
BRD4 protein, human
0
Cell Cycle Proteins
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1114-1125Informations de copyright
©The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
Références
Medchemcomm. 2017 Mar 17;8(6):1322-1331
pubmed: 30108844
Cancer Immunol Res. 2018 Oct;6(10):1234-1245
pubmed: 30087114
Cancer Res. 2013 Oct 15;73(20):6264-76
pubmed: 23950209
Endocrine. 2018 Sep;61(3):407-421
pubmed: 29909598
Pituitary. 2018 Apr;21(2):176-182
pubmed: 29288467
Cureus. 2016 May 21;8(5):e620
pubmed: 27382528
Mol Cancer. 2018 Nov 22;17(1):164
pubmed: 30466442
Cell. 2011 Sep 16;146(6):904-17
pubmed: 21889194
Mol Cell. 2005 Aug 19;19(4):535-45
pubmed: 16109377
J Med Chem. 2018 Jan 25;61(2):462-481
pubmed: 28339196
J Clin Endocrinol Metab. 1994 Jul;79(1):253-7
pubmed: 8027238
Nat Rev Dis Primers. 2019 Mar 21;5(1):20
pubmed: 30899019
Br J Cancer. 2000 Apr;82(8):1441-5
pubmed: 10780524
Mol Endocrinol. 1999 Jan;13(1):156-66
pubmed: 9892021
Drug Discov Today. 2018 Jan;23(1):76-89
pubmed: 28943305
J Chem Inf Model. 2015 Sep 28;55(9):1926-35
pubmed: 26263125
JAMA. 2017 Feb 7;317(5):516-524
pubmed: 28170483
Cancer Res. 2013 Feb 1;73(3):1219-31
pubmed: 23269272
Endocr Relat Cancer. 2019 Jan 1;26(1):13-29
pubmed: 30121620
Brain Pathol. 2001 Jul;11(3):328-41
pubmed: 11414475
J Neurooncol. 2014 May;117(3):421-8
pubmed: 24146188
Nat Rev Endocrinol. 2014 Jul;10(7):423-35
pubmed: 24821329
Endocr Relat Cancer. 2016 Dec;23(12):R551-R566
pubmed: 27697899
Hormones (Athens). 2019 Jun;18(2):117-126
pubmed: 30368687
Brain. 2016 Jul;139(Pt 7):1994-2001
pubmed: 27234268
Cancer Res. 2007 Nov 1;67(21):10564-72
pubmed: 17975001
Histochem Cell Biol. 2008 Sep;130(3):495-507
pubmed: 18688636
Clin Cancer Res. 2018 Sep 1;24(17):4126-4136
pubmed: 30084836
Nature. 2011 Aug 03;478(7370):524-8
pubmed: 21814200
Nat Protoc. 2006;1(5):2315-9
pubmed: 17406473
Cell Death Differ. 2008 Jan;15(1):202-12
pubmed: 17962814
Cell Res. 2015 Mar;25(3):306-17
pubmed: 25675982
Drug Discov Today Technol. 2016 Mar;19:45-50
pubmed: 27769357
Nature. 2010 Dec 23;468(7327):1067-73
pubmed: 20871596
Endocr Pathol. 2012 Jun;23(2):123-31
pubmed: 22327960
Semin Cancer Biol. 2006 Aug;16(4):253-64
pubmed: 16904903
Pituitary. 2017 Feb;20(1):169-178
pubmed: 27987061
J Biol Chem. 2007 May 4;282(18):13141-5
pubmed: 17329240
Mol Cancer Ther. 2014 May;13(5):1142-54
pubmed: 24435446
J Clin Pathol. 1996 Oct;49(10):795-7
pubmed: 8943742
Clin Cancer Res. 2013 Apr 1;19(7):1748-59
pubmed: 23403638
Transcription. 2013 Jan-Feb;4(1):13-7
pubmed: 23131666
Cell. 2012 Mar 30;149(1):214-31
pubmed: 22464331
Cancer Res. 2010 Nov 1;70(21):8748-59
pubmed: 20940401
Cancer Cell. 2015 Jun 8;27(6):837-51
pubmed: 26058079
Neuro Oncol. 2017 Jun 1;19(6):762-773
pubmed: 27543627
J Neurooncol. 2014 May;117(3):379-94
pubmed: 24481996
Cell Rep. 2018 Jan 16;22(3):796-808
pubmed: 29346775
Clin Cancer Res. 2017 Apr 1;23(7):1841-1851
pubmed: 27707790