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Cancer Lett. 2019 Jun 29;461:10-20. doi: 10.1016/j.canlet.2019.06.019. [Epub ahead of print]

Interference with the bromodomain epigenome readers drives p21 expression and tumor senescence.

Author information

1
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, 48109, USA; Department of Oral Pathology, School of Dentistry, Federal University of the Rio Grande do Sul, Porto Alegre, RS, 90035-004, Brazil.
2
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, 48109, USA; Department of Pathology, Federal University of São Paulo, Sao Paulo, SP, 04023-062, Brazil.
3
Oral Diagnosis Department, Piracicaba Dental School, University of Campinas, Piracicaba, SP, 13414-903, Brazil.
4
Department of Oral Pathology, School of Dentistry, Federal University of the Rio Grande do Sul, Porto Alegre, RS, 90035-004, Brazil.
5
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, 48109, USA; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, 48109, USA.
6
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, 48109, USA; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, 48109, USA. Electronic address: rcastilh@umich.edu.

Abstract

Head and neck cancer (HNSCC) are one of the most common solid malignancies of the world, being responsible for over 350,000 deaths every year. Much of the complications in managing and treating HNSCC advent from the complex genetic and epigenetic landscape of the disease. Emerging information has shown promising results in targeting BRD4, an epigenetic regulator bromodomain that functions as a scaffold for transcription factors at promoters and super-enhancers. Here we show that by disrupting the interaction between BRD4 and histones using the bromodomain inhibitor JQ1, HNSCC cells undergo cell growth arrest followed by cellular senescence. Mechanistically, JQ1 negatively impacted the phosphorylation levels of SIRT1 along with the acetylation levels of mutant p53 (active). In vivo administration of JQ1 resulted in disruption of HNSCC growth along with the activation of cellular senescence, observed by the accumulation of DNA double-strand breaks, p16ink4, accumulation of senescence-associated beta-galactosidase, and loss of phosphorylated Sirt1ser47. Furthermore, we also demonstrate that JQ1 was efficient in reducing the population of cancer stem cells from HNSCC xenografts.

KEYWORDS:

Cancer stem cell; Head and neck cancer; Senescence; Tumor suppression; Xenograft

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