N-α-Acetyltransferase 10 Protein Suppresses Cancer Cell Metastasis by Binding PIX Proteins and Inhibiting Cdc42/Rac1 Activity

Abstract

N-α-acetyltransferase 10 protein, Naa10p, is an N-acetyltransferase known to be involved in cell cycle control. We found that Naa10p was expressed lower in varieties of malignancies with lymph node metastasis compared with non-lymph node metastasis. Higher Naa10p expression correlates the survival of lung cancer patients. Naa10p significantly suppressed migration, tumor growth, and metastasis independent of its enzymatic activity. Instead, Naa10p binds to the GIT-binding domain of PIX, thereby preventing the formation of the GIT-PIX-Paxillin complex, resulting in reduced intrinsic Cdc42/Rac1 activity and decreased cell migration. Forced expression of PIX in Naa10-transfected tumor cells restored the migration and metastasis ability. We suggest that Naa10p functions as a tumor metastasis suppressor by disrupting the migratory complex, PIX-GIT- Paxillin, in cancer cells.

Glutathione S-Transferase Mu2 Suppresses Cancer Cell Metastasis in Non–Small Cell Lung Cancer

“…3). A similar recent study indicated that a detoxification phase II acetyltransferase enzyme, N-a-acetyltransferase 10 (Naa10, also known as ARD1), is also indispensable for the suppression of migration, tumor growth, and metastasis in lung cancer cells (42). This highlights the roles of GST-M2 and ARD1 as conserved and essential functions for these enzymes and as repressors or regulators of tumor cell growth and metastasis.…”

Expression of humanNAA11(ARD1B) gene is tissue-specific and is regulated by DNA methylation

“…23 Increased levels of NAA10 transcripts and hNaa10p proteins were respectively found to correlate with better clinical outcome in breast cancer patients 23 and survival of lung cancer patients. 25 Similar to the yeast Naa10p, mouse Naa10p alone does not display NAT activity. 12,26 However, hNaa10p alone was demonstrated to catalyze the acetylation of internal lysine residues in β-Catenin (CTNNB1), 15 Myosin Light Chain Kinase (MLCK), 22 and hNaa10p itself.…”

“…14 A shorter isoform of mNaa10p (mNaa10p_NP_001171436) was shown to stimulate the degradation of Hypoxia Inducible Factor 1a (Hif1α) by acetylating an internal lysine residue of the protein. 27 Interestingly, hNaa10p was shown in lung cancer cells to modulate the activity of DNA Methyltransferase 1 (DNMT1), 21 and to suppress metastasis 25 independently of its acetyltransferase activity. A homolog of Naa10p, called Naa11p (also known as ARREST DEFECTIVE 1B; ARD1B; ARD2), was identified in the mouse 26 and human.…”

“…26 On the other hand, NAA11 was found to co-express with NAA10 in several human cell lines. 17,25,28 The induction of differentiation of promyelocytic leukemia NB4 cells leads to a downregulation of hNaa10p and hNaa15p expression. However, the level of hNaa11p remains unchanged, which implies a role for hNaa11p in the cellular differentiation process.…”

“…17,25,28 NAA11 expression was not detected in the cancerous tissues, with the exception in several cases of relatively weak expression of the gene. On the other hand, NAA10 demonstrated a housekeeping expression pattern in all cases.…”