title: ITPKA Gene Body Methylation Regulates Gene Expression and Serves as an Early Diagnostic Marker in Lung and Other Cancers.
abstract: Despite recent advances in cancer therapy, the overall 5-year survival rate of patients with lung cancer remains low. The aim of our study was to search for novel markers for early diagnosis in patients with lung cancer.
  
  
  
  Complementary DNA microarray analysis was performed in primary lung adenocarcinomas and cell lines to search for differentially expressed genes, followed by in vivo and in vitro tumorigenic assays to characterize the oncogenic potential of the candidate genes. Gene body methylation was analyzed by 450K methylation array, bisulfite sequencing, and quantitative methylation-specific polymerase chain reaction assays. In silico analysis of The Cancer Genome Atlas data set was also performed.
  
  
  
  Inositol-trisphosphate 3-kinase A gene (ITPKA), a kinase with limited tissue distribution, was identified as a potential oncogene. We showed that ITPKA expression is up-regulated in many forms of cancers, including lung and breast cancers, and that overexpressed ITPKA contributes to tumorigenesis. We also demonstrated that ITPKA expression is regulated by epigenetic DNA methylation of ITPKA gene body through modulation of the binding of SP1 transcription factor to the ITPKA promoter. ITPKA gene body displayed low or absent levels of methylation in most normal tissue but was significantly methylated in malignant tumors. In lung cancer, ITPKA gene body methylation first appeared at the in situ carcinoma stage and progressively increased after invasion.
  
  
  
  ITPKA is a potential oncogene that it is overexpressed in most tumors, and its overexpression promotes tumorigenesis. ITPKA gene body methylation regulates its expression and thus serves as a novel and potential biomarker for early cancer detection.
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; Institute of Biomedical Sciences, Academia Sinica, Taipei, Republic of China.
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Wang
authors.affiliation: The Center for Systems Biology, Department of Molecular and Cell Biology, The University of Texas at Dallas, Richardson, Texas.
authors.forename: Xiaotu
authors.initials: X
authors.lastname: Ma
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Yu-An
authors.initials: YA
authors.lastname: Zhang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Republic of China.
authors.forename: Mei-Jung
authors.initials: MJ
authors.lastname: Wang
authors.affiliation: Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.affiliation: British Columbia Cancer Research Center, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Republic of China; Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Republic of China.
authors.forename: Jeou-Yuan
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology and Harold Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: adi.gazdar@utsouthwestern.edu.
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
mesh_terms: D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D019175:DNA Methylation; D055088:Early Detection of Cancer; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase
keywords: Biomarker; Gene body methylation; ITPKA; Oncogene; SP1