title: Expression of microRNA-195 is transactivated by Sp1 but inhibited by histone deacetylase 3 in hepatocellular carcinoma cells.
abstract: MiR-195 expression is frequently reduced in various cancers, but its underlying mechanisms remain unknown. To explore whether abnormal transcription contributed to miR-195 downregulation in hepatocellular carcinoma (HCC), we characterized the -2165-bp site upstream of mature miR-195 as transcription start site and the -2.4 to -2.0-kb fragment as the promoter of miR-195 gene. Subsequent investigation showed that deletion of the predicted Sp1 binding site decreased the miR-195 promoter activity; Sp1 silencing significantly reduced the miR-195 promoter activity and the endogenous miR-195 level; Sp1 directly interacted with the miR-195 promoter in vitro and in vivo. These data suggest Sp1 as a transactivator for miR-195 transcription. Interestingly, miR-195 expression was also subjected to epigenetic regulation. Histone deacetylase 3 (HDAC3) could anchor to the miR-195 promoter via interacting with Sp1 and consequently repress the Sp1-mediated miR-195 transactivation by deacetylating histone in HCC cells. Consistently, substantial increase of HDAC3 protein was detected in human HCC tissues and HDAC3 upregulation was significantly correlated with miR-195 downregulation, suggesting that HDAC3 elevation may represent an important cause for miR-195 reduction in HCC. Our findings uncover the mechanisms underlying the transcriptional regulation and expression deregulation of miR-195 in HCC cells and provide new insight into microRNA biogenesis in cancer cells.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China. Electronic address: zhaonaxiaojie@126.com.
authors.forename: Na
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China. Electronic address: lisiwen128@163.com.
authors.forename: Siwen
authors.initials: S
authors.lastname: Li
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China. Electronic address: 08wangrz@gmail.com.
authors.forename: Ruizhi
authors.initials: R
authors.lastname: Wang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China. Electronic address: moira_xiao@foxmail.com.
authors.forename: Manhuan
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China. Electronic address: mengyu294689775@Gmail.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China. Electronic address: zcx1114@163.com.
authors.forename: Chunxian
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China. Electronic address: van641@163.com.
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Fang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China. Electronic address: lssyje@mail.sysu.edu.cn.
authors.forename: Jine
authors.initials: J
authors.lastname: Yang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, PR China. Electronic address: zhuangshimei@163.com.
authors.forename: Shi-Mei
authors.initials: SM
authors.lastname: Zhuang
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000502:physiology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D035683:MicroRNAs; D016329:Sp1 Transcription Factor; D000099186:Histone Deacetylase 3; C552722:MIRN195 microRNA, human; C108209:SP1 protein, human
keywords: HDAC3; Hepatocellular carcinoma; Non-coding RNA; Sp1; miR-195