title: 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 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.
authors.affiliation: 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].
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.affiliation: 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].
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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].
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Zi-feng
authors.initials: ZF
authors.lastname: Wang
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Fei-meng
authors.initials: FM
authors.lastname: Zheng
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Ming-yuan
authors.initials: MY
authors.lastname: Chen
authors.affiliation: Department of Radiotherapy, Zhongshan Affiliated Hospital of Sun Yat-sen University, Zhongshan 528403, China.
authors.forename: Yu-liang
authors.initials: YL
authors.lastname: Zhu
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Hai-jun
authors.initials: HJ
authors.lastname: Wen
authors.affiliation: Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510635, China.
authors.forename: Xiang-bo
authors.initials: XB
authors.lastname: Wan
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Cai-feng
authors.initials: CF
authors.lastname: Yue
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Jia-liang
authors.initials: JL
authors.lastname: Zhang
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Cancer Stem Cell, First Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University, Dalian 116044, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Cancer Stem Cell, First Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University, Dalian 116044, China.
authors.forename: Lian-hong
authors.initials: LH
authors.lastname: Li
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Yi-xin
authors.initials: YX
authors.lastname: Zeng
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 ONN, UK.
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: 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.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: 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.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D015153:Blotting, Western; D002277:Carcinoma; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000235:genetics; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D034741:RNA, Small Interfering; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D051550:I-kappa B Kinase