title: Histone deacetylase 1/Sp1/microRNA-200b signaling accounts for maintenance of cancer stem-like cells in human lung adenocarcinoma.
abstract: The presence of cancer stem-like cells (CSCs) is one of the mechanisms responsible for chemoresistance that has been a major hindrance towards lung adenocarcinoma (LAD) treatment. Recently, we have identified microRNA (miR)-200b as a key regulator of chemoresistance in human docetaxel-resistant LAD cells. However, whether miR-200b has effects on regulating CSCs remains largely unclear and needs to be further elucidated. Here, we showed that miR-200b was significantly downregulated in CD133+/CD326+ cells that exhibited properties of CSCs derived from docetaxel-resistant LAD cells. Also, restoration of miR-200b could inhibit maintenance and reverse chemoresistance of CSCs. Furthermore, suppressor of zeste-12 (Suz-12) was identified as a direct and functional target of miR-200b, and silencing of Suz-12 phenocopied the effects of miR-200b on CSCs. Additionally, overexpression of histone deacetylase (HDAC) 1 was identified as a pivotal mechanism responsible for miR-200b repression in CSCs through a specificity protein (Sp) 1-dependent mechanism, and restoration of miR-200b by HDAC1 repression significantly suppressed CSCs formation and reversed chemoresistance of CSCs by regulating Suz-12-E-cadherin signaling. Also, downregulation of HDAC1 or upregulation of miR-200b reduced the in vivo tumorigenicity of CSCs. Finally, Suz-12 was inversely correlated with miR-200b, positively correlated with HDAC1 and up-regulated in docetaxel-resistant LAD tissues compared with docetaxel-sensitive tissues. Taken together, the HDAC1/miR-200b/Suz-12-E-cadherin signaling might account for maintenance of CSCs and formation of chemoresistant phenotype in docetaxel-resistant LAD cells.
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, P. R. China.
authors.forename: Dong-Qin
authors.initials: DQ
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, P. R. China.
authors.forename: Jia-Yuan
authors.initials: JY
authors.lastname: Huang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, P. R. China.
authors.forename: Bing
authors.initials: B
authors.lastname: Feng
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, P. R. China.
authors.forename: Ban-Zhou
authors.initials: BZ
authors.lastname: Pan
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: De
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, P. R. China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, P. R. China.
authors.forename: Long-Bang
authors.initials: LB
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009363:Neoplasm Proteins; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D015820:Cadherins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012333:RNA, Messenger; C430461:SUZ12 protein, human; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D014157:Transcription Factors; D063151:Polycomb Repressive Complex 2; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1