Uncovering BRD4 hyperphosphorylation associated with cellular transformation in NUT midline carcinoma.

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.

• Authors: Ranran Wang, Xing-Jun Cao, Katarzyna Kulej, Wei Liu, Tongcui Ma, Margo MacDonald, Cheng-Ming Chiang, Benjamin A Garcia, Jianxin You
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 114 Issue 27 Pg. E5352-E5361 (07 03 2017) ISSN: 1091-6490 [Electronic] United States
• PMID: 28630312 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• BRD4 protein, human
• Cell Cycle Proteins
• NUTM1 protein, human
• Neoplasm Proteins
• Nuclear Proteins
• Oncogene Proteins
• Oncogene Proteins, Fusion
• Transcription Factors
• CDK9 protein, human
• Cyclin-Dependent Kinase 9

Topics

• A549 Cells
• Carcinogenesis
• Carcinoma (drug therapy, genetics, metabolism)
• Cell Cycle Proteins
• Cell Transformation, Neoplastic
• Cyclin-Dependent Kinase 9 (chemistry)
• Drug Screening Assays, Antitumor
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• HeLa Cells
• Humans
• Neoplasm Proteins
• Nuclear Proteins (chemistry, metabolism)
• Oncogene Proteins (metabolism)
• Oncogene Proteins, Fusion (genetics)
• Oncogenes
• Phosphorylation
• Signal Transduction
• Transcription Factors (chemistry)