title: Epigenetic silencing of JMJD5 promotes the proliferation of hepatocellular carcinoma cells by down-regulating the transcription of CDKN1A 686.
abstract: Proteins that contain jumonji C (JmjC) domains have recently been identified as major contributors to various malignant human cancers through epigenetic remodeling. However, the roles of these family members in the pathogenesis of hepatocellular carcinoma (HCC) are obscure. By mining public databases, we found that the HCC patients with lower JmjC domain-containing protein 5 (JMJD5) expression exhibited shorter survival time. We then confirmed that JMJD5 expression was indeed decreased in HCC specimens, which was caused by the altered epigenetic histone modifications, the decreased H3K9ac, H3K27ac and H3K4me2/3 together with the increased trimethylation of H3K27 and H3K9 on the JMJD5 promoter. Functional experiments revealed that JMJD5 knockdown promoted HCC cell proliferation and in vivo tumorigenicity by accelerating the G1/S transition of the cell cycle; in contrast, ectopic JMJD5 expression had the opposite effects. At molecular mechanism, we found that, in HCC cell lines including TP53-null Hep3B, JMJD5 knockdown led to the down-regulation of CDKN1A and ectopic expression of JMJD5 not only increased but also rescued CDKN1A transcription. Moreover, CDKN1A knockdown could abrogate the effect of JMJD5 knockdown or overexpression on cell proliferation, suggesting that JMJD5 inhibits HCC cell proliferation mainly by activating CDKN1A expression. We further revealed that JMJD5 directly enhances CDKN1A transcription by binding to CDKN1A's promoter independent of H3K36me2 demethylase activity. In short, we first prove that JMJD5 is a tumor suppressor gene in HCC pathogenesis, and the epigenetic silencing of JMJD5 promotes HCC cell proliferation by directly down-regulating CDKN1A transcription.
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Bing-Hao
authors.initials: BH
authors.lastname: Wu
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Chun-Miao
authors.initials: CM
authors.lastname: Cai
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Jia-Zhu
authors.initials: JZ
authors.lastname: Fang
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.|Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Chong-Chao
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Li-Yu
authors.initials: LY
authors.lastname: Huang
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.|Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Ze-Guang
authors.initials: ZG
authors.lastname: Han
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D056945:Hep G2 Cells; D064593:Heterografts; D042421:Histone Code; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056466:Histone Demethylases; C550342:KDM8 protein, human
keywords: KDM8; cell cycle; histone modification; transcription; tumorigenicity