Transcriptional repression by the HDAC4-RelB-p52 complex regulates multiple myeloma survival and growth

Subrahmanya D. Vallabhapurapu, The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Sunil K. Noothi, The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Derek A. Pullum, The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Charles H. Lawrie, Department of Oncology, Biodonostia Research Institute, San Sebastián 20014, Spain.
Rachel Pallapati, The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Veena Potluri, The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Christian Kuntzen, Department of Medicine, Bridgeport Hospital, 267 Grant Street, Bridgeport, Connecticut 06610, USA.
Sohaib Khan, The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
David R. Plas, The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Robert Z. Orlowski, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Marta Chesi, Department of Hematology/Oncology , Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale, Arizona 85259, USA.
W Michael Kuehl, Genetics Branch, Center for Cancer Research, National Cancer Institute, Building 37, Room 6002C, Bethesda, Maryland 20892, USA.
P Leif Bergsagel, Department of Hematology/Oncology , Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale, Arizona 85259, USA.
Michael Karin, Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, California 92093, USA.
Sivakumar Vallabhapurapu, The Vontz Center for Molecular Studies, Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.

Document Type

Article

Publication Title

Nature communications

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.

First Page

8428

DOI

10.1038/ncomms9428

Publication Date

10-12-2015

Identifier

26455434 (pubmed); 10.1038/ncomms9428 (doi); ncomms9428 (pii)

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