title: Transcriptional repression by the HDAC4-RelB-p52 complex regulates multiple myeloma survival and growth.
abstract: Although transcriptional activation by NF-κB is well appreciated, physiological importance of transcriptional repression by NF-κB in cancer has remained elusive. Here we show that an HDAC4-RelB-p52 complex maintains repressive chromatin around proapoptotic genes Bim and BMF and regulates multiple myeloma (MM) survival and growth. Disruption of RelB-HDAC4 complex by a HDAC4-mimetic polypeptide blocks MM growth. RelB-p52 also represses BMF translation by regulating miR-221 expression. While the NIK-dependent activation of RelB-p52 in MM has been reported, we show that regardless of the activation status of NIK and the oncogenic events that cause plasma cell malignancy, several genetically diverse MM cells including Bortezomib-resistant MM cells are addicted to RelB-p52 for survival. Importantly, RelB is constitutively phosphorylated in MM and ERK1 is a RelB kinase. Phospho-RelB remains largely nuclear and is essential for Bim repression. Thus, ERK1-dependent regulation of nuclear RelB is critical for MM survival and explains the NIK-independent role of RelB in MM.
authors.affiliation: The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Subrahmanya D
authors.initials: SD
authors.lastname: Vallabhapurapu
authors.affiliation: The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Sunil K
authors.identifier: http://orcid.org/0000-0002-0381-0864
authors.initials: SK
authors.lastname: Noothi
authors.affiliation: The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Pullum
authors.affiliation: Department of Oncology, Biodonostia Research Institute, San Sebastián 20014, Spain.|Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Lawrie
authors.affiliation: The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Pallapati
authors.affiliation: The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Veena
authors.initials: V
authors.lastname: Potluri
authors.affiliation: Department of Medicine, Bridgeport Hospital, 267 Grant Street, Bridgeport, Connecticut 06610, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Kuntzen
authors.affiliation: The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Sohaib
authors.initials: S
authors.lastname: Khan
authors.affiliation: The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Plas
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
authors.affiliation: Department of Hematology/Oncology , Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale, Arizona 85259, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Building 37, Room 6002C, Bethesda, Maryland 20892, USA.
authors.forename: W Michael
authors.initials: WM
authors.lastname: Kuehl
authors.affiliation: Department of Hematology/Oncology , Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale, Arizona 85259, USA.
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, California 92093, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Vallabhapurapu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D051841:Transcription Factor RelB / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D006655:Histone Deacetylases; D008565:Membrane Proteins; D035683:MicroRNAs; D048052:Mitogen-Activated Protein Kinase 3; D052003:NF-kappa B p52 Subunit; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D051841:Transcription Factor RelB; C000606775:BCL2L11 protein, human; C486655:BMF protein, human; C000606776:Bcl2l11 protein, mouse; C525709:MIR221, human; C497593:RELB protein, human; C400300:HDAC4 protein, human