Targeted and interactome proteomics revealed the role of PHD2 in regulating BRD4 proline hydroxylation

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Abstract

Proline hydroxylation is a critical cellular mechanism regulating energy homeostasis and development. Our previous study identified and validated Bromodomain-containing protein 4 (BRD4) as a proline hydroxylation substrate in cancer cells. Yet, the regulatory mechanism and the functional significance of the modification remain unknown. In this study, we developed targeted quantification assays using parallel-reaction monitoring and biochemical analysis to identify the major regulatory enzyme of BRD4 proline hydroxylation. We further performed quantitative interactome analysis to determine the functional significance of the modification pathway in BRD4-mediated protein-protein interactions and gene transcription. Our findings revealed that PHD2 is the key regulatory enzyme of BRD4 proline hydroxylation and the modification significantly affects BRD4 interactions with key transcription factors as well as BRD4-mediated transcriptional activation. Taken together, this study provided mechanistic insights into the oxygen-dependent modification of BRD4 and revealed new roles of the pathway in regulating BRD4-dependent gene expression.

Original languageEnglish (US)
Pages (from-to)1772-1781
Number of pages10
JournalMolecular and Cellular Proteomics
Volume18
Issue number9
DOIs
StatePublished - Sep 2019

Bibliographical note

Funding Information:
* This work was supported by the University of Minnesota research start-up fund (to Y.C.) and the National Institute of Health (1R35GM124896 to Y.C.). □S This article contains supplemental material.

Funding Information:
This work was supported by the University of Minnesota research start-up fund (to Y.C.) and the National Institute of Health (1R35GM124896 to Y.C.).

Publisher Copyright:
© 2019 Erber et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

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