Uncovering BRD4 hyperphosphorylation associated with cellular transformation in NUT midline carcinom1

Ranran Wang, Xing Jun Cao, Katarzyna Kulej, Wei Liu, Tongcui Ma, Margo MacDonald, Cheng Ming Chiang, Benjamin A. Garcia, Jianxin You

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The epigenetic reader BRD4 plays a vital role in transcriptional regulation, cellular growth control, and cell-cycle progression. Dysregulation of BRD4 function has been implicated in the pathogenesis of a wide range of cancers. However, how BRD4 is regulated to maintain its normal function in healthy cells and how alteration of this process leads to cancer remain poorly understood. In this study, we discovered that BRD4 is hyperphosphorylated in NUT midline carcinoma and identified CDK9 as a potential kinase mediating BRD4 hyperphosphorylation. Disruption of BRD4 hyperphosphorylation using both chemical and molecular inhibitors led to the repression of BRD4 downstream oncogenes and abrogation of cellular transformation. BRD4 hyperphosphorylation is also observed in other cancers displaying enhanced BRD4 oncogenic activity. Our study revealed a mechanism that may regulate BRD4 biological function through phosphorylation, which, when dysregulated, could lead to oncogenesis. Our finding points to strategies to target the aberrant BRD4 signaling specifically for cancer intervention.

Original languageEnglish (US)
Pages (from-to)E5352-E5361
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number27
DOIs
StatePublished - Jul 3 2017

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Neoplasms
Cell Cycle Checkpoints
Oncogenes
Epigenomics
Carcinogenesis
Phosphotransferases
Phosphorylation
Carcinoma
Growth

Keywords

  • Bromodomain-containing protein 4
  • Cancer
  • CDK9
  • Cellular transformation
  • NUT midline carcinoma

ASJC Scopus subject areas

  • General

Cite this

Uncovering BRD4 hyperphosphorylation associated with cellular transformation in NUT midline carcinom1. / Wang, Ranran; Cao, Xing Jun; Kulej, Katarzyna; Liu, Wei; Ma, Tongcui; MacDonald, Margo; Chiang, Cheng Ming; Garcia, Benjamin A.; You, Jianxin.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 27, 03.07.2017, p. E5352-E5361.

Research output: Contribution to journalArticle

Wang, Ranran ; Cao, Xing Jun ; Kulej, Katarzyna ; Liu, Wei ; Ma, Tongcui ; MacDonald, Margo ; Chiang, Cheng Ming ; Garcia, Benjamin A. ; You, Jianxin. / Uncovering BRD4 hyperphosphorylation associated with cellular transformation in NUT midline carcinom1. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 27. pp. E5352-E5361.
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