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

Abstract

Although transcriptional activation by NF-kB is well appreciated, physiological importance of transcriptional repression by NF-kB 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.

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

“…The potential impact of our results is related to emerging findings on the prognostic weight and potential as therapeutic targets of HDACs in multiple myeloma, as shown by recent work demonstrating a significantly shorter progression-free survival of multiple myeloma patients with higher levels of class I/II HDACs (40); moreover, class II HDAC inhibition was proven to enhance the anti-multiple myeloma activity of ER stressors, such as carfilzomib (41), whereas peptide-mediated disruption of HDAC4/RelB complex was found to block multiple myeloma growth (42). In this light, we here provide novel findings unraveling the molecular and functional role of HDAC4 and its regulation in multiple myeloma cells.…”

Aberrant Expression of Histone Deacetylases 4 in Cognitive Disorders: Molecular Mechanisms and a Potential Target

“…In addition to synaptic plasticity, HDAC4 is also involved in neuronal apoptosis. For example, HDAC4 interacts with NF-κB repressing proapoptotic gene expression, and it also inhibit ER stress-induced apoptosis by interacting with activating transcription factor 4 (ATF4), a key transcriptional factor in ER stress response ( Figure 1 ) (Zhang et al, 2014; Vallabhapurapu et al, 2015). Moreover, Majdzadeh et al (2008) showed that HDAC4 overexpression protects mouse cerebellar granule neurons (CGNs) from apoptosis by inhibiting cyclin dependent kinase 1 (CDK1) activity.…”

Mechanisms of NF-κB deregulation in lymphoid malignancies

“…Of note, 50% of the somatic mutations in MM lead to inactivation or deletion of TRAF3 resulting in high NIK protein levels [45,47]. Elimination of NIK, RelB or p52 is highly toxic to HL and MM cells, underscoring the importance of non-canonical signaling for survival of the lymphomas [49,52]. Recent comparative analyses revealed a substantial cross-talk of canonical and non-canonical NF-B signaling in lymphoma.…”

“…RelB is a substrate of MALT1 in ABC DLBCL and RelB overexpression impairs survival of ABC DLBCL suggesting that noncanonical counteracts canonical NF-B signaling and survival of ABC DLBCL [102]. However, non-canonical NF-B was suggested to act oncogenic in HL, MM and DLBCL (see Section 4) and thus the reason for the tumor suppressing function of RelB in ABC DLBCL awaits further analyses [49,52]. New data indicate that the MALT1 protease may also regulate the LUBAC that was shown to control CBM mediated IKK activation in DLBCL [88].…”