NAT10-mediated ac4C acetylation promotes the proliferation and migration of breast cancer cells
Objective To investigate the specific mechanism of N-acetyltransferase 10(NAT10)-mediated acetylation modification of N4-acetylcytidine(ac4C)promoting the proliferation and migration of breast cancer cells.Methods 80 cases of breast cancer and corresponding paracancerous tissues were collected.The expression of NAT10 and the level of ac4C modifica-tion in tissues and cell lines were detected.The relationship between NAT 10 expression and clinicopathological features of breast cancer was analyzed.The proliferation,migration,invasion capabilities,and cell cycle changes of SKBR-3 and BT474 cells were evaluated through in vitro cell experiments.The tumorigenic capacity of cells was determined through xenograft experiments in vivo,with the expression of Ki-67 in transplanted tumors detected and the formation of tumor nodules in the liver and lungs ob-served.The gene expression profile mediated by NAT10-induced ac4C acetylation modification was analyzed,and the effect of NAT 10 on KIF23 expression through ac4C modification was verified.The expression of proteins related to the NAT10/KIF23/GSK-3β axis and the Wnt/β-catenin signaling pathway was detected.Results The expression level of NAT 10 and the level of ac4C modification in breast cancer tissues and cell lines were higher than those in paracancerous tissues and MCF-10A cells(P＜0.05).The expression of NAT 10 was correlated with tumor stage,lymphatic metastasis,distant metastasis,degree of differentiation,and Ki-67 positivity rate(P＜0.05).Inhibiting NAT 10 expression was found to suppress the proliferation,migration,and invasion ca-pabilities of SKBR-3 cells,arrest cell cycle progression,and reduce tumorigenicity and metastasis ability in vivo.Conversely,overexpressing NAT10 promoted the malignant biological behavior of BT474 cells.KIF23 was identified as a direct target of NAT 10 with ac4C modification,and a positive correlation was observed between the expression levels of the two proteins(r=0.3624,P=0.0010).Both inhibition and overexpression of NAT10 were found to affect the interaction between NAT10 and KIF23,as well as the ac4C modification of KIF23 mRNA(P＜0.05).Inhibiting NAT10 while overexpressing KIF23,or overex-pressing NAT10 while inhibiting KIF23,was able to reverse the effects of NAT10 expression level changes on the proliferation,migration,invasion,cell cycle,and expression of Wnt/β-catenin signaling pathway-related proteins in SKBR-3 and BT474 cells.Conclusion NAT10-mediated ac4C acetylation modification enhances KIF23 expression,and the NAT10/KIF23/GSK-3β axis promotes the occurrence and development of breast cancer by regulating the Wnt/β-catenin signaling pathway.
N-acetyltransferase 10N4-acetylcytidineacetylation modificationbreast cancerkinesin family member 23
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