NAT10 Promotes the Malignant Progression of Hepatocellular Carcinoma through Upregulating RelA/p65 Acetylation

Abstract

Purposes: N-acetyltransferase 10 (NAT10), a newly discovered specific N-acetyl transferase, plays a vital role in human disease. However, its role in the malignant progression of hepatocellular carcinoma (HCC) has not been fully elucidated. Methods: We first investigated the expression of NAT10 in HCC and the correlation between the expression of NAT10 and patient prognosis by using multiple groups of clinical tissues combined with data from The Cancer Genome Atlas (TCGA) database. We next constructed stable cell lines from HCC cells to confirm the tumor-promoting effects of NAT10 in HCC. In addition, we conducted various molecular experiments combined with mass spectrometry and transcriptome sequencing were conducted to further explore the internal molecular mechanism of NAT10 enhancing the HCC malignant process. Results: We found that NAT10 expression was markedly elevated in HCC tissues and the elevated levels of NAT10 were associated with worse prognoses in HCC patients. Cell function experiments showed that NAT10 overexpression enhanced HCC cell proliferation and migration, implying that NAT10 promoted the malignant progression of HCC. Furthermore, a sorafenib killing experiment showed that knocking out NAT10 enhanced the drug sensitivity of Hep3B cells. In addition, after overexpression of NAT10 in SMMC-7721 cells, the cells were significantly more resistant to sorafenib. Our study also showed that NAT10 activated the nuclear factor-kappa B (NF-κB) signaling pathway by directly binding RelA/p65 to promote lysine 310 acetylation. Moreover, NAT10 promoted HCC proliferation by promoting acetyl-NF-κB p65 (Lys310) in vivo and in vitro. Conclusions: Our study showed that NAT10 promoted the occurrence and development of HCC, which provides a corresponding theoretical basis for subsequent related research and translational application.