title: Human Helicase RECQL4 Drives Cisplatin Resistance in Gastric Cancer by Activating an AKT-YB1-MDR1 Signaling Pathway.
abstract: Elevation of the DNA-unwinding helicase RECQL4, which participates in various DNA repair pathways, has been suggested to contribute to the pathogenicity of various human cancers, including gastric cancer. In this study, we addressed the prognostic and chemotherapeutic significance of RECQL4 in human gastric cancer, which has yet to be determined. We observed significant increases in RECQL4 mRNA or protein in >70% of three independent sets of human gastric cancer specimens examined, relative to normal gastric tissues. Strikingly, high RECQL4 expression in primary tumors correlated well with poor survival and gastric cancer lines with high RECQL4 expression displayed increased resistance to cisplatin treatment. Mechanistic investigations revealed a novel role for RECQL4 in transcriptional regulation of the multidrug resistance gene MDR1, through a physical interaction with the transcription factor YB1. Notably, ectopic expression of RECQL4 in cisplatin-sensitive gastric cancer cells with low endogenous RECQL4 was sufficient to render them resistant to cisplatin, in a manner associated with YB1 elevation and MDR1 activation. Conversely, RECQL4 silencing in cisplatin-resistant gastric cancer cells with high endogenous RECQL4 suppressed YB1 phosphorylation, reduced MDR1 expression, and resensitized cells to cisplatin. In establishing RECQL4 as a critical mediator of cisplatin resistance in gastric cancer cells, our findings provide a therapeutic rationale to target RECQL4 or the downstream AKT-YB1-MDR1 axis to improve gastric cancer treatment. Cancer Res; 76(10); 3057-66. ©2016 AACR.
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Mo
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Fang
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Niu
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Biological Institute, Hebei Academy of Sciences, Shijiazhuang, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Shiyou
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang, China.
authors.forename: Tienian
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, City Hospital Campus, Nottingham, United Kingdom.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Aleskandarany
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, City Hospital Campus, Nottingham, United Kingdom.
authors.forename: Arvind
authors.initials: A
authors.lastname: Arora
authors.affiliation: Gastrointestinal Surgery, National Institute for Health Research Nottingham Digestive Diseases Centre, Biomedical Research Unit, Nottingham University Hospitals and University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom.
authors.forename: Dileep N
authors.initials: DN
authors.lastname: Lobo
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, City Hospital Campus, Nottingham, United Kingdom.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
authors.affiliation: REAC/TS, Oak Ridge Associated Universities, Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee.
authors.forename: Adayabalam S
authors.initials: AS
authors.lastname: Balajee
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. zhaoyongliang@big.ac.cn chizf@big.ac.cn.
authors.forename: Zhenfen
authors.initials: Z
authors.lastname: Chi
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. zhaoyongliang@big.ac.cn chizf@big.ac.cn.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D053484:RecQ Helicases / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D051840:Y-Box-Binding Protein 1 / Q000378:metabolism*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C506731:RECQL4 protein, human; D053484:RecQ Helicases; D002945:Cisplatin