title: Global Oct4 target gene analysis reveals novel downstream PTEN and TNC genes required for drug-resistance and metastasis in lung cancer.
abstract: Overexpression of Oct4, a stemness gene encoding a transcription factor, has been reported in several cancers. However, the mechanism by which Oct4 directs transcriptional program that leads to somatic cancer progression remains unclear. In this study, we provide mechanistic insight into Oct4-driven transcriptional network promoting drug-resistance and metastasis in lung cancer cell, animal and clinical studies. Through an integrative approach combining our Oct4 chromatin-immunoprecipitation sequencing and ENCODE datasets, we identified the genome-wide binding regions of Oct4 in lung cancer at promoter and enhancer of numerous genes involved in critical pathways which promote tumorigenesis. Notably, PTEN and TNC were previously undefined targets of Oct4. In addition, novel Oct4-binding motifs were found to overlap with DNA elements for Sp1 transcription factor. We provided evidence that Oct4 suppressed PTEN in an Sp1-dependent manner by recruitment of HDAC1/2, leading to activation of AKT signaling and drug-resistance. In contrast, Oct4 transactivated TNC independent of Sp1 and resulted in cancer metastasis. Clinically, lung cancer patients with Oct4 high, PTEN low and TNC high expression profile significantly correlated with poor disease-free survival. Our study reveals a critical Oct4-driven transcriptional program that promotes lung cancer progression, illustrating the therapeutic potential of targeting Oc4 transcriptionally regulated genes.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, No.1, University Road, Tainan 701, Taiwan Department of Pharmacology, National Cheng Kung University, No.1, University Road, Tainan 701, Taiwan.
authors.forename: Yen-An
authors.initials: YA
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, National Cheng Kung University, No.1, University Road, Tainan 701, Taiwan.
authors.forename: Chi-Hsin
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan 701, Taiwan.
authors.forename: H Sunny
authors.initials: HS
authors.lastname: Sun
authors.affiliation: Department of Computer Science and Information Engineering, National Cheng Kung University, No.1, University Road, Tainan 701, Taiwan.
authors.forename: Chun-Pei
authors.initials: CP
authors.lastname: Cheng
authors.affiliation: Department of Computer Science and Information Engineering, National Cheng Kung University, No.1, University Road, Tainan 701, Taiwan Institute of Medical Informatics, College of Electrical Engineering and Computer Science, National Cheng Kung University, No.1, University Road, Tainan 701, Taiwan.
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Tseng
authors.affiliation: Division of Thoracic Surgery, Taipei Veterans General Hospital; Institute of Emergency and Critical Care Medicine, National Yang-Ming University School of Medicine, No.155, Sec.2, Linong Street, Taipei 112, Taiwan.
authors.forename: Han-Shui
authors.initials: HS
authors.lastname: Hsu
authors.affiliation: Department of Internal Medicine, National Cheng Kung University Hospital, No.138, Sheng Li Road, Tainan 704, Taiwan.
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
authors.affiliation: Department of Surgery, National Cheng Kung University Hospital, No.138, Sheng Li Road, Tainan 704, Taiwan.
authors.forename: Wu-Wei
authors.initials: WW
authors.lastname: Lai
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, No.1, University Road, Tainan 701, Taiwan Department of Pharmacology, National Cheng Kung University, No.1, University Road, Tainan 701, Taiwan ycw5798@mail.ncku.edu.tw.
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Wang
mesh_terms: D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics*; D050814:Octamer Transcription Factor-3 / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D019063:Tenascin / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D019063:Tenascin; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human