NatB-mediated protein N-α-terminal acetylation is a potential therapeutic target in hepatocellular carcinoma

Oncotarget
Leire NeriRafael Aldabe

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 interestin...Continue Reading

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Citations

Jul 29, 2018·Experimental & Molecular Medicine·Rasmus ReeThomas Arnesen
Nov 1, 2020·International Journal of Molecular Sciences·Sun Myung KimJi Hae Seo
Jan 6, 2021·Communications Biology·Dominik LayerIrmgard Sinning
Jun 22, 2021·Frontiers in Oncology·Costas Koufaris, Antonis Kirmizis
Jul 8, 2021·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Jennifer MorrisonThomas Arnesen

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Methods Mentioned

BETA
acetylating
acetylation
transfection
xenograft
nuclear translocation
surgical resection
PCR
Assay
flow cytometry

Software Mentioned

SPSS
GraphPad
Matlab
Image Studio Lite
Prism

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