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

Subrahmanya D. Vallabhapurapu, Sunil K. Noothi, Derek A. Pullum, Charles H. Lawrie, Rachel Pallapati, Veena Potluri, Christian Kuntzen, Sohaib Khan, David R. Plas, Robert Z. Orlowski, Marta Chesi, W. Michael Kuehl, P. Leif Bergsagel, Michael Karin and Sivakumar Vallabhapurapu ()
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Subrahmanya D. Vallabhapurapu: The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine
Sunil K. Noothi: The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine
Derek A. Pullum: The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine
Charles H. Lawrie: Biodonostia Research Institute
Rachel Pallapati: The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine
Veena Potluri: The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine
Christian Kuntzen: Bridgeport Hospital
Sohaib Khan: The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine
David R. Plas: The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine
Robert Z. Orlowski: The University of Texas MD Anderson Cancer Center
Marta Chesi: Mayo Clinic
W. Michael Kuehl: Genetics Branch, Center for Cancer Research, National Cancer Institute
P. Leif Bergsagel: Mayo Clinic
Michael Karin: Laboratory of Gene Regulation and Signal Transduction, University of California
Sivakumar Vallabhapurapu: The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9428

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