title: Alterations in histone deacetylase 8 lead to cell migration and poor prognosis in breast cancer.
abstract: OBJECTIVE
  Alterations in histone proteins can lead to breast tumorigenesis. Selective histone deacetylase 8 (HDAC8) inhibitors with fewer adverse effects have been developed. A more comprehensive study of alterations and its mechanisms in HDAC8 is required. In this study, we investigated mechanisms of dysregulation of HDAC8 expression and its biological role and pathways in breast cancer.
  
  
  METHODS
  Alterations in HDAC8 were analyzed in Taiwanese breast cancer patients; and in tissue samples from The Cancer Genome Atlas (TCGA) data set that were derived from Western countries. Knockdown by si-HDAC8, treatment with the HDAC8-specific inhibitor PCI-34051, SRB assays, wound healing, Transwell migration assays, Illumina BeadArray™ arrays and Ingenuity Pathway Analysis (IPA) were performed in breast cancer cells.
  
  
  RESULTS
  HDAC8 mRNA expression was upregulated in paired breast cancer tissue from Taiwanese patients and in paired breast cancer tissues from the TCGA data set. Hypomethylation of promoter regions was significantly correlated with HDAC8 mRNA overexpression in 588 breast cancer patients from the TCGA data set and was associated with poor prognosis in early-stage breast cancer. HDAC8 mRNA overexpression was associated with late stages and tumor progression. Wound healing and Transwell migration assays revealed that knockdown by si-HDAC8 or PCI-34051 treatment significantly inhibited breast cancer cell migration. Knockdown by si-HDAC8, Illumina BeadArray™ arrays and IPA found that ID3 and PTP4A2 pathways were regulated by HDAC8 in cancer cell migration.
  
  
  CONCLUSIONS
  Hypomethylation of the HDAC8 promoter is correlated with HDAC8 overexpression and breast cancer progression and is a potential prognosis marker and drug target.
authors.affiliation: Professional Master Program in Pharmaceutics and Biotechnology, Taipei Medical University, Taipei 110, Taiwan, ROC.
authors.forename: Chang-Lin
authors.initials: CL
authors.lastname: Hsieh
authors.affiliation: Emergency Department, Shuang Ho Hospital, New Taipei City 235, Taiwan, ROC; Department of Emergency Medicine, School of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC.
authors.forename: Hon-Ping
authors.initials: HP
authors.lastname: Ma
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC; Department of Surgery, Taipei Medical University Shuang Ho Hospital, Taipei 235, Taiwan, ROC.
authors.forename: Chih-Ming
authors.initials: CM
authors.lastname: Su
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC.
authors.forename: Yu-Jia
authors.initials: YJ
authors.lastname: Chang
authors.affiliation: Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, Taipei Medical University, Taipei 110, Taiwan, ROC.
authors.forename: Wan-Yu
authors.initials: WY
authors.lastname: Hung
authors.affiliation: Graduate Institute of Biomedical Technology, Comprehensive Cancer Center, Taipei Medical University, Taipei 110, Taiwan, ROC.
authors.forename: Yuan-Soon
authors.initials: YS
authors.lastname: Ho
authors.affiliation: Graduate Institute of Pharmacognosy, Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, Taipei 110, Taiwan, ROC.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.affiliation: Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, Taipei Medical University, Taipei 110, Taiwan, ROC; Graduate Institute of Pharmacognosy, Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, Taipei 110, Taiwan, ROC. Electronic address: linruokai@tmu.edu.tw.
authors.forename: Ruo-Kai
authors.initials: RK
authors.lastname: Lin
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055785:Gene Knockdown Techniques; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases
keywords: Breast cancer; Cell migration; DNA methylation; HDAC8; IPA; PCI-34051; TCGA; Tamoxifen