miR-375-NAT10 Axis Dysfunction Promotes Oral Cancer Development and Mediates Cdk7 Stabilizing and Cell Cycle Progression

Abstract

Background: Oral cancer is the most common cancer with poor prognosis and outcome for the patients due to the challenging diagnosis and limited treatment possibilities. However, the molecular underpinnings behind the malignant progression of oral cancer remain incompletely understood. Methods: The expression profiling of NAT10 and CDK7 in oral cancer patients were assessed by IHC, qPCR and western blots. ShRNA was used to silence gene expression. The biological function of NAT10 and CDK7 in cholangiocarcinoma was investigated using in vitro and in vivo studies including, transwell cell migration, plate cloning, CCK8, shRNA interference, western blots, flow cytometry and xenograft mouse model. The underlying molecular mechanism was determined by western blots and immunoprecipitation.Results: In this study, we demonstrated that deregulation of miR-375-NAT10 axis is among the most causes in inducing the acquisition of a tumorigenesis phenotype in oral cancer cells. NAT10 is abundant in oral cancer tissue. and its protein level is positively correlated with poor overall survival. Increased the level of NAT10 promotes oral cancer cell proliferation in vitro as well as xenograft tumorigenicity in vivo. Most importantly, NAT10 regulates cancer cell proliferation through stabilizing CDK7 thus regulating the cell cycle. NAT10 as an acetyltransferase is responsible for CDK7 acetylation at lysine 328 (K328Ac). Moreover, it was found that the expression of miR-375 is abnormally alleviated in oral cancer tissues. Bioinformatics analysis revealed a targeted complementary binding site between miR-375 and NAT10. Decreased expression of miR-375 promotes expression of NAT10.Conclusion: Our study showed that NAT10 plays a strong carcinogenic role in oral cancer tumorigenesis by acetylating CDK7 at K382 thus promotion stability. Moreover, NAT10 may serve as a target for miR-375. Therefore, targeting NAT10 may provide a new and effective therapeutic strategy to inhibit the tumorigenicity of oral cancer.