IKKalpha restoration via EZH2 suppression induces nasopharyngeal carcinoma differentiation.

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 IKKalpha expression is responsible for the undifferentiated phenotype of NPC. Conversely, overexpression of IKKalpha induces differentiation and reduces tumorigenicity of NPC cells without activating NF-kappaB signalling. Importantly, we describe a mechanism whereby EZH2 directs IKKalpha transcriptional repression via H3K27 histone methylation on the IKKalpha promoter. The differentiation agent, retinoic acid, increases IKKalpha expression by suppressing EZH2-mediated H3K27 histone methylation, resulting in enhanced differentiation of NPC cells. In agreement, an inverse correlation between IKKalpha (low) and EZH2 (high) expression is associated with a lack of differentiation in NPC patient samples. Collectively, these findings demonstrate a role for IKKalpha in NPC differentiation and reveal an epigenetic mechanism for IKKalpha regulation, unveiling a new avenue for differentiation therapy.