title: BRD4 short isoform interacts with RRP1B, SIPA1 and components of the LINC complex at the inner face of the nuclear membrane.
abstract: 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.
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jude
authors.initials: J
authors.lastname: Alsarraj
authors.forename: Farhoud
authors.initials: F
authors.lastname: Faraji
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Geiger
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Mattaini
authors.forename: Mia
authors.initials: M
authors.lastname: Williams
authors.forename: Josephine
authors.initials: J
authors.lastname: Wu
authors.forename: Ngoc-Han
authors.initials: NH
authors.lastname: Ha
authors.forename: Tyler
authors.initials: T
authors.lastname: Merlino
authors.forename: Renard C
authors.initials: RC
authors.lastname: Walker
authors.forename: Allen D
authors.initials: AD
authors.lastname: Bosley
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xiao
authors.forename: Thorkell
authors.initials: T
authors.lastname: Andresson
authors.forename: Dominic
authors.initials: D
authors.lastname: Esposito
authors.forename: Nicholas
authors.initials: N
authors.lastname: Smithers
authors.forename: Dave
authors.initials: D
authors.lastname: Lugo
authors.forename: Rab
authors.initials: R
authors.lastname: Prinjha
authors.forename: Anup
authors.initials: A
authors.lastname: Day
authors.forename: Nigel P S
authors.initials: NP
authors.lastname: Crawford
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.forename: Kevin
authors.initials: K
authors.lastname: Gardner
authors.forename: Kent W
authors.initials: KW
authors.lastname: Hunter
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D063213:N-Terminal Acetyltransferase E / Q000378:metabolism; D063206:N-Terminal Acetyltransferases; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009685:Nuclear Envelope / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms; D021381:Protein Transport; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D000092468:Bromodomain Containing Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D020690:GTPase-Activating Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D063213:N-Terminal Acetyltransferase E; D063206:N-Terminal Acetyltransferases; D009687:Nuclear Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C568713:GSK1210151A; C574722:RRP1B protein, human; C490403:SIPA1 protein, human; C506117:SUN1 protein, human; C413025:SUN2 protein, human; C522989:NAT10 protein, human