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Cell Oncol (Dordr). 2019 Apr;42(2):143-155. doi: 10.1007/s13402-018-0416-2. Epub 2018 Dec 11.

Interfering with bromodomain epigenome readers as therapeutic option in mucoepidermoid carcinoma.

Author information

1
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, 1011 N University Ave, Room 2029C, Ann Arbor, MI, 48109-1078, USA.
2
Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas-UNICAMP, Piracicaba, Brazil.
3
Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul-UFRGS, Porto Alegre, RS, 90035-003, Brazil.
4
Genetics and Molecular Biology Research Unit, Sao Jose do Rio Preto Medical School-FAMERP, Sao Jose do Rio Preto, Brazil.
5
Head and Neck Department, Santa Rita Hospital - Santa Casa de Misericordia de Porto Alegre, Porto Alegre, RS, Brazil.
6
Comprehensive Cancer Center, University of Michigan Ann Arbor, Ann Arbor, MI, 48109, USA.
7
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, 1011 N University Ave, Room 2029C, Ann Arbor, MI, 48109-1078, USA. rcastilh@umich.edu.
8
Comprehensive Cancer Center, University of Michigan Ann Arbor, Ann Arbor, MI, 48109, USA. rcastilh@umich.edu.

Abstract

PURPOSE:

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.

METHODS:

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 p16ink4. Flow cytometry was used to identify populations of cancer stem cells in MEC-derived cell lines.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

BRD4; Cancer stem cells; Epi-drug; Epigenetic; Mucoepidermoid carcinoma; iBET762

PMID:
30539410
DOI:
10.1007/s13402-018-0416-2

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