N-acetyltransferase 10 Promotes Pancreatic Cancer Progression Through ZEB1/MT1-MMP Axis

To elucidate the role of N-acetyltransferase 10 (NAT10) in pancreatic cancer (PC) progression and its epigenetic mechanisms, particularly in relation to metastasis.

TCGA and GTEx databases were used to analyze the expression and roles of NAT10 in pancreatic cancer. We constructed stable cell lines with NAT10 knockdown in PC cell lines, AsPC-1 and KPC. CCK-8, EdU assay, and colony formation assay were conducted to evaluate the capability of cell proliferation and clonogenesis in vitro. Meanwhile, a transwell assay was performed to assess the impact on invasion and metastasis abilities. The correlation between NAT10 and ZEB1 expression was verified by correlation analysis. The underlying mechanisms through which NAT10 regulates ZEB1 were confirmed by qPCR, western blot, RIP-qPCR, dot plot, and mRNA stability assay. Furthermore, the interplay among NAT10, ZEB1, and MT1-MMP was confirmed using similar experimental approaches. Rescue experiments involving ZEB1 overexpression further verified the role of NAT10/ZEB1/MT1-MMP axis in PC metastasis. In addition, the NAT10 inhibitor Remodelin was employed in a nude orthotopic PC model to investigate its effects on metastasis in vivo.

NAT10 was found to be upregulated in PC and was significantly associated with poor prognosis. After NAT10 knockdown, the ability of proliferation and metastasis of AsPC-1 and KPC was remarkably impaired, the degree of ac4C modification was decreased, and the mRNA stability of ZEB1 declined. Correlation analysis indicated a positive correlation among NAT10, ZEB1, and MT1-MMP, and the results of qPCR and western blot also verified this conclusion. Moreover, ZEB1 overexpression could significantly reverse the inhibition of migration and invasion induced by NAT10 depletion in AsPC-1. NAT10 inhibitor Remodelin treatment could reduce the degree of peritoneal and liver metastases in vivo.

Our study highlights the pivotal functions of NAT10 in the progression of PC and reveals the underlying epigenetic mechanism that NAT10 promotes metastasis via ZEB1/MT1-MMP axis.