Journal Article

BRD4 Short Isoform Interacts with RRP1B, SIPA1 and Components of the LINC Complex at the Inner Face of the Nuclear Membrane

Crawford, Nigel P. S., Merlino, Tyler, Hunter, Kent W., Geiger, Thomas R., Lugo, Dave, Prinjha, Rab, Ozato, Keiko, Faraji, Farhoud, Day, Anup, Xiao, Zhen, Gardner, Kevin, Bosley, Allen D., Andresson, Thorkell, Alsarraj, Jude, Ha, Ngoc-Han, Esposito, Dominic, Mattaini, Katherine R., Williams, Mia, Walker, Renard C., Smithers, Nicholas, Wu, Josephine

2013

Overview

Recent studies suggest that BET inhibitors are effective anti-cancer therapeutics. Here we show that BET inhibitors are effective against murine primary mammary tumors, but not pulmonary metastases. BRD4, a target of BET inhibitors, encodes two isoforms with opposite effects on tumor progression. To gain insights into why BET inhibition was ineffective against metastases the pro-metastatic short isoform of BRD4 was characterized using mass spectrometry and cellular fractionation. Our data show that the pro-metastatic short isoform interacts with the LINC complex and the metastasis-associated proteins RRP1B and SIPA1 at the inner face of the nuclear membrane. Furthermore, histone binding arrays revealed that the short isoform has a broader acetylated histone binding pattern relative to the long isoform. These differential biochemical and nuclear localization properties revealed in our study provide novel insights into the opposing roles of BRD4 isoforms in metastatic breast cancer progression.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Anticancer properties / Apoptosis Regulatory Proteins - metabolism / Binding / Biology / Breast cancer / Cancer / Cancer metastasis / Cancer treatment / Cell Cycle Proteins / Cell Line, Tumor / Cell Nucleus - metabolism / Childrens health / Chromosomal Proteins, Non-Histone - metabolism / Development and progression / Disease Models, Animal / Extracellular matrix / Female / Fractionation / Gene expression / Genetics / Genomes / GTPase-Activating Proteins - metabolism / Heterocyclic Compounds, 4 or More Rings - pharmacology / Histones - metabolism / Humans / Inflammation / Inhibitors / Intracellular Signaling Peptides and Proteins - metabolism / Isoforms / Laboratories / Localization / Mass spectrometry / Mass spectroscopy / Medical prognosis / Medical research / Membrane Proteins - metabolism / Metastases / Metastasis / Mice / Microtubule-Associated Proteins - metabolism / Mortality / N-Terminal Acetyltransferase E - metabolism / N-Terminal Acetyltransferases / Neoplasm Metastasis / Neoplasms - metabolism / Neoplasms - pathology / Nuclear Envelope - metabolism / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Pharmacology / Protein Binding / Protein Isoforms / Protein Transport / Proteins / Proteomics / Transcription Factors - genetics / Transcription Factors - metabolism / Tumor Burden - drug effects / Tumors