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

Subrahmanya D Vallabhapurapu,Rachel Pallapati,David R Plas,Marta Chesi,P Leif Bergsagel,Veena Potluri,Sivakumar Vallabhapurapu,Derek A Pullum,Christian Kuntzen,Robert Z Orlowski,W Michael Kuehl,Charles H Lawrie,Michael Karin,Sunil K Noothi,Sohaib Khan

doi:10.1038/ncomms9428

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.

Highlights

Transcriptional activation by NF-kB is well appreciated, physiological importance of transcriptional repression by NF-kB in cancer has remained elusive
In a subset of MM cell lines (MMCLs), mutations leading to NF-kB inducing kinase (NIK) stabilization were reported[23]
Within these NIKhigh MMCLs, IKKb, a kinase that regulates the classical RelAp50 pathway was shown to be essential for survival, whereas depletion of IKKa, an essential kinase for RelB-p52 activation had no effect on MM cell survival[23]

Summary

Introduction

Transcriptional activation by NF-kB is well appreciated, physiological importance of transcriptional repression by NF-kB in cancer has remained elusive. Identification of novel gene regulatory NF-kB complexes that are essential for the maintenance of repressive chromatin and tumour growth will enable us to develop novel therapeutic approaches for cancer cure. Classical NF-kB complexes (RelA-p50) have been well studied for their role in tumour survival and growth, but the relative contribution of the alternative NF-kB (RelB-p52) in cancer has been unclear. Another report suggested that targeting IKKa impairs MM tumour growth without influencing NF-kB activation[30] These reports suggested that downstream of NIK, activation of IKKb-dependent classical NF-kB plays an important role in MM-cell survival whereas the role of IKKa-dependent RelB-p52 pathway in MM remained elusive. While some reports indicated HDAC3 and HDAC6 as attractive drug targets in MM37,38, it is not clear which HDAC is commonly required for the survival of most genetic subgroups of MM cells

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Conclusion