IKKa restoration via EZH2 suppression induces nasopharyngeal carcinoma differentiation

Abstract

Lack of cellular differentiation is a key feature of nasopharyngeal carcinoma (NPC), but it also presents as a unique opportunity for intervention by differentiation therapy. Here using RNA-seq profiling analysis and functional assays, we demonstrate that reduced IKKa expression is responsible for the undifferentiated phenotype of NPC. Conversely, overexpression of IKKa induces differentiation and reduces tumorigenicity of NPC cells without activating NF-kB signalling. Importantly, we describe a mechanism whereby EZH2 directs IKKa transcriptional repression via H3K27 histone methylation on the IKKa promoter. The differentiation agent, retinoic acid, increases IKKa expression by suppressing EZH2-mediated H3K27 histone methylation, resulting in enhanced differentiation of NPC cells. In agreement, an inverse correlation between IKKa (low) and EZH2 (high) expression is associated with a lack of differentiation in NPC patient samples. Collectively, these findings demonstrate a role for IKKa in NPC differentiation and reveal an epigenetic mechanism for IKKa regulation, unveiling a new avenue for differentiation therapy. © 2014 Macmillan Publishers Limited.