Inhibition of N-Acetyltransferase 10 Suppresses the Progression of Prostate Cancer through Regulation of DNA Replication

Abstract

Cancer suppression through the inhibition of N-acetyltransferase 10 (NAT10) by its specific inhibitor Remodelin has been demonstrated in a variety of human cancers. Here, we report the inhibitory effects of Remodelin on prostate cancer (PCa) cells and the possible associated mechanisms. The prostate cancer cell lines VCaP, LNCaP, PC3, and DU145 were used. The in vitro proliferation, migration, and invasion of cells were measured by a cell proliferation assay, colony formation, wound healing, and Transwell assays, respectively. In vivo tumor growth was analyzed by transplantation into nude mice. The inhibition of NAT10 by Remodelin not only suppressed growth, migration, and invasion in vitro, but also the in vivo cancer growth of prostate cancer cells. The involvement of NAT10 in DNA replication was assessed by EdU labeling, DNA spreading, iPOND, and ChIP-PCR assays. The inhibition of NAT10 by Remodelin slowed DNA replication. NAT10 was detected in the prereplication complex, and it could also bind to DNA replication origins. Furthermore, the interaction between NAT10 and CDC6 was analyzed by Co-IP. The altered expression of NAT10 was measured by immunofluorescence staining and Western blotting. Remodelin markedly reduced the levels of CDC6 and AR. The expression of NAT10 could be altered under either castration or noncastration conditions, and Remodelin still suppressed the growth of in vitro-induced castration-resistant prostate cancers. The analysis of a TCGA database revealed that the overexpression of NAT10, CDC6, and MCM7 in prostate cancers were correlated with the Gleason score and node metastasis. Our data demonstrated that Remodelin, an inhibitor of NAT10, effectively inhibits the growth of prostate cancer cells under either no castration or castration conditions, likely by impairing DNA replication.

The positive feedback loop of the NAT10/Mybbp1a/p53 axis promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury

“…This is strongly supported by some studies showing that Remodelin inhibits ac4C RNA levels and NAT10 expression in human immunodeficiency virus and cancer [ [42] , [43] , [44] ]. Contrary to this consensus, a few studies have reported that NAT10 expression cannot be altered by Remodelin [ 45 , 46 ]. Our study showed that Remodelin markedly reduced the acetyltransferase activity of NAT10, which is necessary for catalyzing RNA acetylation, as indicated by reduced levels of ac4C in total RNA and reduced levels of ac4C in Mybbp1a mRNA in I/R-exposed hearts and H/R-exposed cardiomyocytes.…”

NAT10-mediated RNA ac4C acetylation contributes to the myocardial infarction induced cardiac fibrosis

“…Similar to the MI group, the sham-operated mice experienced the same experimental procedures without ligation of LAD. According to a previous study [13], remodelin (2 mg/kg) was dissolved in DMSO and administered to the animals by i.p. injection every two days for 4 weeks.…”

Unleashing Ferroptosis in Human Cancers: Targeting Ferroptosis Suppressor Protein 1 for Overcoming Therapy Resistance

“…NAT10 plays a vital role in activating ribosomal RNA biogenesis, and its activity is inhibited by deacetylation mediated by sirtuin 1 [ 54 ]. Aberrant NAT10 expression is associated with the occurrence and prognosis of various cancers [ 55 , 56 ]; the inhibition of NAT10 suppresses tumor progression [ 57 ]. The knockdown of NAT10 promotes ferroptosis and inhibits proliferation and metastasis in colon cancer cells, which can be reversed by ferroptosis inhibition both in vitro and in vivo [ 53 ].…”