NatB-mediated protein N-α-terminal acetylation is a potential therapeutic target in hepatocellular carcinoma
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Leire Neri1, Marta Lasa1, Alberto Elosegui-Artola2, Delia D'Avola3,4, Beatriz Carte1, Cristina Gazquez1, Sara Alve5, Pere Roca-Cusachs2,6, Mercedes Iñarrairaegui3,4, Jose Herrero3,4, Jesús Prieto1,3, Bruno Sangro3,4 and Rafael Aldabe1,4
1Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain
2Institute for Bioengineering of Catalonia, Barcelona, Spain
3Liver Unit, Clínica Universidad de Navarra, Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (Ciberehd), Pamplona, Spain
4Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
5Department of Biology, CBMA-Centre of Molecular and Environmental Biology, University of Minho, Campus de Gualtar, Braga, Portugal
6University of Barcelona, Barcelona, Spain
Rafael Aldabe, email: firstname.lastname@example.org
Keywords: tropomyosin, CDK2, focal adhesions, cell-cell junctions, cell cycle arrest
Received: December 21, 2016 Accepted: April 04, 2017 Published: April 21, 2017
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.
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