IKKα restoration via EZH2 suppression induces nasopharyngeal carcinoma differentiation

Min Yan, Yan Zhang, Bin He, Jin Xiang, Zi-feng Wang, Fei-meng Zheng, Jie Xu, Ming-yuan Chen, Yu-liang Zhu, Hai-jun Wen, Xiang-bo Wan, Cai-feng Yue, Na Yang, Wei Zhang, Jia-liang Zhang, Jing Wang, Yang Wang, Lian-hong Li, Yi-xin Zeng, Eric W.-F. Lam, Mien-Chie Hung and Quentin Liu ()
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Min Yan: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Yan Zhang: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Bin He: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Jin Xiang: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Zi-feng Wang: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Fei-meng Zheng: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Jie Xu: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Ming-yuan Chen: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Yu-liang Zhu: Zhongshan Affiliated Hospital of Sun Yat-sen University
Hai-jun Wen: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Xiang-bo Wan: The Third Affiliated Hospital, Sun Yat-sen University
Cai-feng Yue: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Na Yang: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Wei Zhang: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Jia-liang Zhang: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Jing Wang: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Yang Wang: Institute of Cancer Stem Cell, First Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University
Lian-hong Li: Institute of Cancer Stem Cell, First Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University
Yi-xin Zeng: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine
Eric W.-F. Lam: Imperial College London, Hammersmith Hospital Campus
Mien-Chie Hung: The University of Texas M.D. Anderson Cancer Center
Quentin Liu: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4661

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