Interfering with bromodomain epigenome readers as therapeutic option in mucoepidermoid carcinoma.
Adolescent
Adult
Aged
Benzodiazepines
/ pharmacology
Carcinoma, Mucoepidermoid
/ drug therapy
Cell Cycle Proteins
Cell Line, Tumor
Cellular Senescence
/ drug effects
Epigenesis, Genetic
/ drug effects
Female
Histones
/ metabolism
Humans
Male
Middle Aged
Models, Biological
Molecular Targeted Therapy
Neoplastic Stem Cells
/ drug effects
Nuclear Proteins
/ metabolism
Signal Transduction
/ drug effects
Transcription Factors
/ metabolism
Tumor Stem Cell Assay
Young Adult
BRD4
Cancer stem cells
Epi-drug
Epigenetic
Mucoepidermoid carcinoma
iBET762
Journal
Cellular oncology (Dordrecht)
ISSN: 2211-3436
Titre abrégé: Cell Oncol (Dordr)
Pays: Netherlands
ID NLM: 101552938
Informations de publication
Date de publication:
Apr 2019
Apr 2019
Historique:
accepted:
19
11
2018
pubmed:
13
12
2018
medline:
30
7
2019
entrez:
13
12
2018
Statut:
ppublish
Résumé
Emerging evidence indicates that bromodomains comprise a conserved class of epigenome readers involved in cancer development and inflammation. Bromodomains are associated with epigenetic modifications of gene transcription through interactions with lysine residues of histone tails. Particularly, the bromodomain and extra-terminal domain (BET) family member BRD4 has been found to be involved in the control over oncogenes, including c-MYC, and in the maintenance of downstream inflammatory processes. The objective of this study was to evaluate the effect of pharmacologically displacing BRD4 in mucoepidermoid carcinoma (MEC) cells. We assessed the presence of BRD4 levels in a panel of human MEC tissue samples in conjunction with histological grading and clinical information. In vitro studies were carried out using human MEC-derived cell lines. The BET inhibitor iBET762 was administered to MEC cells to assess the impact of disrupted BRD4 signaling on colony forming capacities and cell cycle status. The activation of cellular senescence induced by iBET762 was determined by immunohistochemical staining for p16 We found that primary human MECs and MEC-derived cell lines are endowed with high BRD4 expression levels compared to those in normal salivary glands. We also found that, by displacing BRD4 from chromatin using the BET inhibitor iBET762, MEC cells lose their colony forming capacities and undergo G1 cell cycle arrest and senescence. Finally, we found that targeted displacement of BRD4 from chromatin results in depletion of cancer stem cells from the overall MEC cell populations. Our findings indicate that bromodomain-mediated gene regulation constitutes an epigenetic mechanism that is deregulated in MEC cells and that the use of BET inhibitors may serve as a feasible therapeutic strategy to manage MECs.
Identifiants
pubmed: 30539410
doi: 10.1007/s13402-018-0416-2
pii: 10.1007/s13402-018-0416-2
doi:
Substances chimiques
BRD4 protein, human
0
Cell Cycle Proteins
0
Histones
0
Nuclear Proteins
0
Transcription Factors
0
Benzodiazepines
12794-10-4
molibresib
5QIO6SRZ2R
Types de publication
Journal Article
Langues
eng
Pagination
143-155Subventions
Organisme : School of Dentistry, University of Michigan
ID : N/A
Organisme : CAPES
ID : BEX / 88881.132606/2016-01 PDSE
Organisme : NCI NIH HHS
ID : P30 CA046592
Pays : United States
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