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

Leire Neri,Marta Lasa,Delia D'Avola,Pere Roca-Cusachs,Jesús Prieto,Rafael Aldabe,Bruno Sangro,Jose Herrero,Beatriz Carte,Sara Alve,Alberto Elosegui-Artola,Mercedes Iñarrairaegui,Cristina Gazquez

doi:10.18632/oncotarget.17332

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.

Highlights

Acetylation is a post-translational modification of cellular proteins consisting of covalent binding of an acetyl group from an acetyl-CoA donor
We found that hNatB is required for N-α-terminal acetylation of two tropomyosin isoforms, tropomyosin 1.6 (TPM 1.6) and tropomyosin 2.1 (TPM 2.1) and that inhibition of hNatB causes the disruption of focal and intercellular adhesions, blocking cell cycle progression in association with degradation of CDK2, a cyclin-dependent kinase that is a hNatB substrate
N-terminal acetylation is a co/post-translational modification of proteins that is essential for their stability and function. hNatB mediates N-terminal acetylation of specific proteins, which are recognized by specific amino acid sequence at the N-terminus

Summary

Introduction

Acetylation is a post-translational modification of cellular proteins consisting of covalent binding of an acetyl group from an acetyl-CoA donor. This reaction is catalyzed by two families of acetyltransferases: lysine acetyltransferases (KATs) [1] and alpha-aminoterminal acetyltransferases (NATs) [2]. Upregulation of the NatA catalytic subunit, NAA10, has been reported in lung, breast and urinary bladder cancers as well as in cervical carcinoma and HCC in association with poor survival and tumor aggressiveness [5]. Our group has previously shown that in HCC, the expression of the NatB catalytic subunit NAA20 correlates with tumor progression [12]. In addition several authors have observed a direct correlation between NatB subunits expression and cellular proliferation [13, 14]

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Conclusion