title: Aberrant KDM5B expression promotes aggressive breast cancer through MALAT1 overexpression and downregulation of hsa-miR-448.
abstract: BACKGROUND
  Triple negative breast cancers (TNBC) possess cell dedifferentiation characteristics, carry out activities connate to those of cancer stem cells (CSCs) and are associated with increased metastasis, as well as, poor clinical prognosis. The regulatory mechanism of this highly malignant phenotype is still poorly characterized. Accruing evidence support the role of non-coding RNAs (ncRNAs) as potent regulators of CSC and metastatic gene expression, with their dysregulation implicated in tumorigenesis and disease progression.
  
  
  METHODS
  In this study, we investigated TNBC metastasis, metastasis-associated genes and potential inhibitory mechanisms using bioinformatics, tissue microarray analyses, immunoblotting, polymerase chain reaction, loss and gain of gene function assays and comparative analyses of data obtained.
  
  
  RESULTS
  Compared with other breast cancer types, the highly metastatic MDA-MB-231 cells concurrently exhibited increased expression levels of Lysine-specific demethylase 5B protein (KDM5B) and long non-coding RNA (lncRNA), MALAT1, suggesting their functional association. KDM5B-silencing in the TNBC cells correlated with the upregulation of hsa-miR-448 and led to suppression of MALAT1 expression with decreased migration, invasion and clonogenic capacity in vitro, as well as, poor survival in vivo. This projects MALAT1 as a mediator of KDM5B oncogenic potential and highlights the critical role of this microRNA, lncRNA and histone demethylase in cancer cell motility and metastatic colonization. Increased expression of KDM5B correlating with disease progression and poor clinical outcome in breast cancer was reversed by hsa-miR-448.
  
  
  CONCLUSIONS
  Our findings demonstrate the critical role of KDM5B and its negative regulator hsa-miR-448 in TNBC metastasis and progression. Hsa-miR-448 disrupting KDM5B-MALAT1 signalling axis and associated activities in TNBC cells, projects it as a putative therapeutic factor for selective eradication of TNBC cells. Graphical abstract KDM5B, MALAT1 and hsa-miR-448 are active looped components of the epigenetic poculo mortis in aggressive breast cancer.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan. dr_bamodu@yahoo.com.|Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan. dr_bamodu@yahoo.com.
authors.forename: Oluwaseun Adebayo
authors.initials: OA
authors.lastname: Bamodu
authors.affiliation: Department of Thoracic Surgery, Mackay Memorial Hospital, Taipei, 10449, Taiwan. wjhuang0@yahoo.com.tw.
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Department of Pathology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan. whlpath97616@s.tmu.edu.tw.
authors.forename: Wei-Hwa
authors.initials: WH
authors.lastname: Lee
authors.affiliation: Graduate Institute of Translational Medicine, Taipei Medical University, Taipei City, Taiwan. chaw1211@tmu.edu.tw.|The PhD Program of Translational Medicine, Academia Sinica, Nankang, Taipei, Taiwan. chaw1211@tmu.edu.tw.
authors.forename: Alexander
authors.initials: A
authors.lastname: Wu
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan. wangls72269@yahoo.com.tw.|Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan. wangls72269@yahoo.com.tw.
authors.forename: Liang Shun
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan. mhsiao@gate.sinica.edu.tw.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan. ctyeh@s.tmu.edu.tw.|Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan. ctyeh@s.tmu.edu.tw.
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan. j0607@ms6.hinet.net.|Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan. j0607@ms6.hinet.net.|Tri-Service General Hospital, Neihu District, Taipei City, Taiwan. j0607@ms6.hinet.net.
authors.forename: Tsu-Yi
authors.initials: TY
authors.lastname: Chao
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016000:Cluster Analysis; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D056484:Jumonji Domain-Containing Histone Demethylases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000737:chemistry / Q000235:genetics*; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology
chemical_list: C557041:MALAT1 long non-coding RNA, human; C557400:MIRN448 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D012097:Repressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human