NatB-mediated protein N-α-terminal acetylation is a potential therapeutic target in hepatocellular carcinoma
| Autor: | Pere Roca-Cusachs, Sara Alve, Marta Lasa, Bruno Sangro, José Ignacio Herrero, Alberto Elosegui-Artola, Leire Neri, Cristina Gazquez, Delia D'Avola, Beatriz Carte, Mercedes Iñarrairaegui, Rafael Aldabe, Jesús Prieto |
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| Přispěvatelé: | Universitat de Barcelona |
| Rok vydání: | 2017 |
| Předmět: |
CDK2
Motilitat cel·lular 0301 basic medicine Carcinoma Hepatocellular Tropomyosin Cell motility Biology Transfection Càncer de fetge Focal adhesion Adherens junction 03 medical and health sciences chemistry.chemical_compound Cell Movement Proteïnes citosquelètiques Humans cell-cell junctions Cytoskeleton N-Terminal Acetyltransferase B Regulation of gene expression Focal Adhesions Cell growth Liver Neoplasms Acetylation Adherens Junctions Cell Cycle Checkpoints Actin cytoskeleton Cytoskeletal proteins 3. Good health 030104 developmental biology Oncology chemistry cell cycle arrest Tumor progression Cancer research Growth inhibition Liver cancer Research Paper |
| Zdroj: | Oncotarget Dipòsit Digital de la UB Universidad de Barcelona Recercat. Dipósit de la Recerca de Catalunya instname |
| ISSN: | 1949-2553 |
| Popis: | // Leire Neri 1 , Marta Lasa 1 , Alberto Elosegui-Artola 2 , Delia D'Avola 3, 4 , Beatriz Carte 1 , Cristina Gazquez 1 , Sara Alve 5 , Pere Roca-Cusachs 2, 6 , Mercedes Inarrairaegui 3, 4 , Jose Herrero 3, 4 , Jesus Prieto 1, 3 , Bruno Sangro 3, 4 and Rafael Aldabe 1, 4 1 Gene Therapy and Regulation of Gene Expression Program, Centro de Investigacion Medica Aplicada, Universidad de Navarra, Pamplona, Spain 2 Institute for Bioengineering of Catalonia, Barcelona, Spain 3 Liver Unit, Clinica Universidad de Navarra, Centro de Investigacion Biomedica en Red en el Area Tematica de Enfermedades Hepaticas y Digestivas (Ciberehd), Pamplona, Spain 4 Instituto de Investigacion Sanitaria de Navarra (IdiSNA), Pamplona, Spain 5 Department of Biology, CBMA-Centre of Molecular and Environmental Biology, University of Minho, Campus de Gualtar, Braga, Portugal 6 University of Barcelona, Barcelona, Spain Correspondence to: Rafael Aldabe, email: raldabe@unav.es Keywords: tropomyosin, CDK2, focal adhesions, cell-cell junctions, cell cycle arrest Received: December 21, 2016 Accepted: April 04, 2017 Published: April 21, 2017 ABSTRACT The identification of new targets for systemic therapy of hepatocellular carcinoma (HCC) is an urgent medical need. Recently, we showed that hNatB catalyzes the N-α-terminal acetylation of 15% of the human proteome and that this action is necessary for proper actin cytoskeleton structure and function. In tumors, cytoskeletal changes influence motility, invasion, survival, cell growth and tumor progression, making the cytoskeleton a very attractive antitumor target. Here, we show that hNatB subunits are upregulated in in over 59% HCC tumors compared to non-tumor tissue and that this upregulation is associated with microscopic vascular invasion. We found that hNatB silencing blocks proliferation and tumor formation in HCC cell lines in association with hampered DNA synthesis and impaired progression through the S and the G2/M phases. Growth inhibition is mediated by the degradation of two hNatB substrates, tropomyosin and CDK2, which occurs when these proteins lack N-α-terminal acetylation. In addition, hNatB inhibition disrupts the actin cytoskeleton, focal adhesions and tight/adherens junctions, abrogating two proliferative signaling pathways, Hippo/YAP and ERK1/2. Therefore, inhibition of NatB activity represents an interesting new approach to treating HCC by blocking cell proliferation and disrupting actin cytoskeleton function. |
| Databáze: | OpenAIRE |
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