title: NEK9-dependent proliferation of cancer cells lacking functional p53.
abstract: Dysfunction of the p53 network is a major cause of cancer development, and selective elimination of p53-inactivated cancer cells therefore represents an ideal therapeutic strategy. In this study, we performed a microRNA target screen that identified NEK9 (NIMA-related kinase 9) as a crucial regulator of cell-cycle progression in p53-inactivated cancer cells. NEK9 depletion selectively inhibited proliferation in p53-deficient cancer cells both in vitro and in vivo. The resultant cell-cycle arrest occurred predominantly in G1 phase, and exhibited senescence-like features. Furthermore, NEK9 repression affected expression of a broad range of genes encoding cell-cycle regulators and factors involved in mRNA processing, suggesting a novel role for NEK9 in p53-deficient cells. Lung adenocarcinoma patients with positive staining for NEK9 and mutant p53 proteins exhibited significantly poorer prognoses, suggesting that expression of both proteins promotes tumor growth. Our findings demonstrate that a novel NEK9 network regulates the growth of cancer cells lacking functional p53.
authors.affiliation: 1] Division of Genome Biology, National Cancer Center Research Institute [2] Laboratory for Medical Engineering, Division of Materials and Chemical Engineering, Graduate School of Engineering, Yokohama National University, 79-1 Tokiwadai, Hodogaya-ku Yokohama 240-8501, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kurioka
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Takeshita
authors.affiliation: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku Tokyo 104-0045.
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuta
authors.affiliation: Division of Genetics, National Cancer Center Research Institute.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakamoto
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku Tokyo 104-0045.
authors.forename: Shun-ichi
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Division of Allergy &Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura Setagaya-ku Tokyo, 157-8535.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Laboratory for Medical Engineering, Division of Materials and Chemical Engineering, Graduate School of Engineering, Yokohama National University, 79-1 Tokiwadai, Hodogaya-ku Yokohama 240-8501, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
authors.affiliation: 1] Division of Genome Biology, National Cancer Center Research Institute [2] Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona, Spain.
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute.
authors.forename: Naoto
authors.initials: N
authors.lastname: Tsuchiya
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D048308:Mitogen-Activated Protein Kinase 14 / Q000096:biosynthesis; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C462119:NEK9 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases; D048308:Mitogen-Activated Protein Kinase 14