GSK-3β–Regulated N-Acetyltransferase 10 Is Involved in Colorectal Cancer Invasion

Abstract

Purpose: NAT10 (N-acetyltransferase 10) is a nucleolar protein, but may show subcellular redistribution in colorectal carcinoma. In this study, we evaluated membranous staining of NAT10 in colorectal carcinoma and its clinical implications, and explored the mechanism of regulation of NAT10 redistribution.Experimental Design: The expression and subcellular redistribution of NAT10, b-catenin, E-cadherin, and GSK-3b were evaluated by immunohistochemistry in 222 cases of colorectal carcinoma. Regulation of NAT10 and its influence on cell motility were analyzed with inhibitors of GSK-3b, transfection of wild-type or kinase-inactivated GSK-3b, or expression of various domains of NAT10, and evaluated with immunofluorescence, Western blotting, and Transwell assays.Results: NAT10 localized mainly in the nucleoli of normal tissues, and was redistributed to the membrane in cancer cells, particularly at the invasive "leading edge" of the tumor. This correlated well with nuclear accumulation of b-catenin (P < 0.001; x 2 ¼ 68.213). In addition, NAT10 membrane staining reflected the depth of invasion and tendency to metastasize (all P values < 0.001), and was associated with a poorer prognosis (P ¼ 0.023; x 2 ¼ 5.161). Evaluation of the mechanism involved demonstrated that subcellular redistribution of NAT10 may result from its increased stability and nuclear export, which is brought about by inhibition of GSK-3b. Moreover, redistribution of NAT10 induces alteration of cytoskeletal dynamics and increases cancer cell motility. Conclusion:The subcellular redistribution of NAT10 can be induced by decreases in GSK-3b activity. This redistribution increases cancer cell motility, and is, thus, correlated with invasive potential and poorer clinical outcome. This finding suggests that NAT10 may be a useful prognostic marker and potential therapeutic target in colorectal carcinoma.

Human NAT10 Is an ATP-dependent RNA Acetyltransferase Responsible for N4-Acetylcytidine Formation in 18 S Ribosomal RNA (rRNA)

“…Moreover, NAT10 is highly expressed in malignant tumors (19,21), and it is essential for growth of a subtype of epithelial ovarian cancer with poor prognosis (22). Recent work demonstrated that NAT10 is the molecular target of a chemical compound called "Remodelin," which treats laminopathies, including premature aging syndromes, by correcting nuclear architecture (20).…”

Yeast Kre33 and human NAT10 are conserved 18S rRNA cytosine acetyltransferases that modify tRNAs assisted by the adaptor Tan1/THUMPD1

“…The salient features of this emerging class of human diseases are an increased pre-disposition to cancer and hematopoiesis and skeletons defects ( 81 ). NAT10 has been implicated in the DNA damage response, telomerase function and cytokinesis and reported as a cancer biomarker ( 31 , 34 – 35 ). Recently, inactivation of NAT10 has been shown to suppress morphological nuclear shape abnormalities associated with mutations in laminopathic cells, notably from patients with premature-aging progeria syndrome ( 30 ).…”

“…It has also been attributed a regulatory role in telomerase function and in the DNA damage response ( 31 – 34 ). NAT10 is a cancer biomarker whose overexpression in various soft tissue sarcomas strikingly correlates with tumor histological grading ( 31 ) and whose subcellular distribution is a potential prognostic marker in colorectal carcinoma ( 35 ). Remarkably, NAT10 inactivation was recently shown to suppress the nuclear shape defects associated with lamin mutations in laminopathic patient cells ( 30 ).…”

Inhibition of NAT10 Suppresses Melanogenesis and Melanoma Growth by Attenuating Microphthalmia-Associated Transcription Factor (MITF) Expression

“…N -acetyltransferase 10 (NAT10), a member of GCN5-related N -acetyltransferases (GNAT), has been reported to be involved in the regulation of ribosome biogenesis, histone acetylation, DNA damage response, microtubule reorganization, and cell cycle progression [ 1 , 2 , 3 , 4 ]. The expression of NAT10 is reported to increase in response to DNA damage, and ectopic expression of NAT10 maintains cell survival upon DNA damage stress [ 5 ].…”