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Nat Commun. 2014 Apr 17;5:3661. doi: 10.1038/ncomms4661.

IKKα restoration via EZH2 suppression induces nasopharyngeal carcinoma differentiation.

Author information

1
1] Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China [2].
2
1] Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China [2] Institute of Cancer Stem Cell, First Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University, Dalian 116044, China [3].
3
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
4
Department of Radiotherapy, Zhongshan Affiliated Hospital of Sun Yat-sen University, Zhongshan 528403, China.
5
Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510635, China.
6
Institute of Cancer Stem Cell, First Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University, Dalian 116044, China.
7
Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 ONN, UK.
8
1] Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA [2] Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan.
9
1] Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China [2] Institute of Cancer Stem Cell, First Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University, Dalian 116044, China.

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

PMID:
24739462
DOI:
10.1038/ncomms4661
[Indexed for MEDLINE]

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