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

Nat Commun. 2015 Oct 12;6:8428. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Bcl-2-Like Protein 11
  • Gene Expression Regulation, Neoplastic*
  • Histone Deacetylases / metabolism*
  • Male
  • Membrane Proteins / genetics
  • Mice, Nude
  • MicroRNAs / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Multiple Myeloma / metabolism*
  • NF-kappa B p52 Subunit / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcription Factor RelB / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • BMF protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • MIRN221 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • NF-kappa B p52 Subunit
  • Proto-Oncogene Proteins
  • RELB protein, human
  • Repressor Proteins
  • Transcription Factor RelB
  • Mitogen-Activated Protein Kinase 3
  • HDAC4 protein, human
  • Histone Deacetylases