IKKα 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.

IKKα-mediated biogenesis of miR-196a through interaction with Drosha regulates the sensitivity of cancer cells to radiotherapy

“…19,20 To examine whether IKKα is activated in radioresistant NPC cells, the phosphorylation levels of IKKα at S176/S180 and T23 sites were detected by western blot. Surprisingly, we found that the expression level of p-IKKαT23 in both C666-S8GY and C666-M2GY cells was significantly decreased while the phosphorylation of IKKα at S176/S180 sites was unchanged as compared with C666-1 control cells (Figure 1e).…”

miRNA-1290 Promotes Aggressiveness in Pancreatic Ductal Adenocarcinoma by Targeting IKK1

“…In PDAC, NF-kB is constitutively activated in most patients and is linked to a KRAS mutation via the IKK1 complex [40,41]. As a tumor-related gene, the role of IKK1 in nasopharyngeal carcinoma differentiation is complex [42]. Its expression is almost negative in keratinizing nasopharyngeal carcinoma but higher in non-keratinizing nasopharyngeal carcinoma [42].…”

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

“…[7,9,10] Alternatively, IKKα suppresses carcinogenesis in the skin, lungs, esophagi, nasopharynges, and pancreas of humans and mice independently of canonical and noncanonical NF-kB pathways ( Figure 1B). [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] These findings highlight the medical importance of IKK/NF-kB in the pathogenesis of human diseases and malignancies.…”

“…Severe autoimmunity and systemic autoinflammation Tumors in the esophagus and oral cavity/ fungal infection [25,35,36] Skin, lung, esophgeal, oral, and pancreatic cancer [15][16][17][18][19][20][21][22][23][24][25][26][27][28] www.advancedsciencenews.com www.bioessays-journal.com NF-kB pathways. [1,13,14,[48][49][50] The thymus of Ikkα À/À newborns show reduced medullary regions and mTEC numbers.…”