title: RNA helicase YTHDC2 promotes cancer metastasis via the enhancement of the efficiency by which HIF-1α mRNA is translated.
abstract: YTH domain containing 2 (YTHDC2) is a member of the DExD/H-box family of ATP-dependent RNA helicases. We previously found that YTHDC2 expression is up-regulated in several human cancer cells. In this study, we demonstrate novel roles for YTHDC2 in metastasis of colon tumor cells via translation-dependent pathway. Knockdown of YTHDC2 attenuated protein expression of metastasis-related genes, such as hypoxia-inducible factor-1alpha (HIF-1α), and inhibited metastasis of colon tumor cells in vitro and in vivo. To confirm that YTHDC2 promotes translation initiation by unwinding the 5'-untranslated region (5'UTR) of mRNA, we constructed a firefly luciferase reporter containing the 5'UTR of the HIF-1α mRNA and showed reduction in luciferase activity in YTHDC2-silenced cells. Furthermore, we examined expression levels of YTHDC2 by immunohistochemical staining in human colon cancer tissues from 72 patients and found a significantly positive correlation between YTHDC2 expression and the tumor stage, including metastasis. In conclusion, these results suggest that the RNA helicase YTHDC2 contributes to colon tumor metastasis by promoting translation of HIF-1α and that YTHDC2 is potentially a diagnostic marker and target gene for treating colon cancer patients.
authors.affiliation: Laboratory of Biology, Azabu University School of Veterinary Medicine, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanabe
authors.affiliation: Laboratory of Biology, Azabu University School of Veterinary Medicine, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.
authors.forename: Kenya
authors.initials: K
authors.lastname: Tanikawa
authors.affiliation: Laboratory of Biology, Azabu University School of Veterinary Medicine, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Tsunetomi
authors.affiliation: Laboratory of Biology, Azabu University School of Veterinary Medicine, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Takai
authors.affiliation: Laboratory of Biology, Azabu University School of Veterinary Medicine, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Laboratory of Biology, Azabu University School of Veterinary Medicine, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.
authors.forename: Junpei
authors.initials: J
authors.lastname: Konno
authors.affiliation: Department of Pathology, Public Health Sapporo Medical University School of Medicine, South 1 West 17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Torigoe
authors.affiliation: Department of Surgery, Public Health Sapporo Medical University School of Medicine, South 1 West 17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Maeda
authors.affiliation: Department of Surgery, Public Health Sapporo Medical University School of Medicine, South 1 West 17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Goro
authors.initials: G
authors.lastname: Kutomi
authors.affiliation: Department of Surgery, Public Health Sapporo Medical University School of Medicine, South 1 West 17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Okita
authors.affiliation: Public Health Sapporo Medical University School of Medicine, South 1 West 17, Chuo-ku, Sapporo 060-8556, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Mori
authors.affiliation: Laboratory of Biology, Azabu University School of Veterinary Medicine, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan. Electronic address: sahara@azabu-u.ac.jp.
authors.forename: Hiroeki
authors.initials: H
authors.lastname: Sahara
mesh_terms: D020121:5' Untranslated Regions; D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002465:Cell Movement; D002522:Chlorocebus aethiops; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D045325:HCT116 Cells; D019073:HT29 Cells; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism; D020365:RNA Helicases; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D000072258:Tumor Hypoxia; D051879:Twist-Related Protein 1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D020121:5' Untranslated Regions; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D012333:RNA, Messenger; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D000251:Adenosine Triphosphatases; D020365:RNA Helicases; C562343:YTHDC2 protein, human
keywords: Colon tumor; HIF-1α; Metastasis; RNA helicase