NatD contains only a single catalytic unit, Naa40p, and has no auxiliary subunit 3, 11. NatD (also termed Nat4 or Patt1) mediates the Nt-acetylation of histone H4 and H2A exclusively, differentiating it from all other Nat family members, which target various substrates 8, 9, 10. In humans, six different NATs (NatA-NatF) have been identified to date based on their unique subunits and specific substrates 3. Nt-acetylation is catalyzed by N-α-acetyltransferases (NATs), which transfer the acetyl group from acetyl-coenzyme A (Ac-CoA) to the primary α-amino group of the N-terminal amino acid residue of a protein. This modification has a variety of biological roles, including regulation of protein degradation, protein–protein interactions, protein translocation, membrane attachment, apoptosis, and cellular metabolism 3, 5, 6, 7. N-α-terminal acetylation (Nt-acetylation) is one of the most common protein covalent modifications in eukaryotes, occurring in 80–90% of soluble proteins in humans and 50–70% in yeast 1, 2, 3, 4. These findings indicate that NatD is a crucial epigenetic modulator of cell invasion during lung cancer progression. Importantly, NatD is commonly upregulated in primary human lung cancer tissues where its expression level correlates with Slug expression, enhanced invasiveness, and poor clinical outcomes. We found that Nt-acetylation of histone H4 antagonizes histone H4 serine 1 phosphorylation (H4S1ph), and that downregulation of Nt-acetylation of histone H4 facilitates CK2α binding to histone H4 in lung cancer cells, resulting in increased H4S1ph and epigenetic reprogramming to suppress Slug transcription to inhibit EMT. Depletion of NatD suppresses the epithelial-to-mesenchymal transition (EMT) of lung cancer cells by directly repressing the expression of transcription factor Slug, a key regulator of EMT. Here we report that NatD promotes the migratory and invasive capabilities of lung cancer cells in vitro and in vivo. N-α-acetyltransferase D (NatD) mediates N-α-terminal acetylation (Nt-acetylation) of histone H4 known to be involved in cell growth.

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