Epigenetic Inactivation of Acetyl-Co A acetyltransferase 1 promotes the proliferation and metastasis of nasopharyngeal carcinoma via decreasing ketogenesis

Background Acy1 Coenzyme A Acyltransferases1 (ACAT1) is a key enzyme in the metabolism of ketone bodies, but its expression and biological function in the pathogenesis of NPC remains underexplored. Methods The mRNA and protein expression levels of ACAT1 in NPC and normal control tissues were analyzed by qPCR and immunohistochemistry staining, respectively. GEO database was applied for meta-analysis of ACAT1 mRNA expression and DNA promoter methylation. The role of ACAT1 in NPC proliferation was examined by CCK8 and colony formation assays in vitro and tumorigenicity in vivo. The wound healing and transwell assays were used for analyzing the migratory and invasive ability. cDNA microarray analysis was performed to identify the genes involved in epithelial-mesenchymal transition and dysregulated by ACAT1. These changes were further confirmed by western blot. Results We found that ACAT1 is inactivated in NPC cell lines and primary tissues. DNA microarray data showed higher methylation in the CpG island region of ACAT1 in NPC than normal tissues. The demethylating reagent 5-aza-dC significantly restored the transcription of ACAT1 in NPC cell lines, suggesting that ACAT1 was inactivated by DNA promoter hypermethylation. Ectopic overexpression of ACAT1 remarkably suppressed the proliferation and colony formation of NPC cells in vitro. As well, the tumorigenesis of NPC cells overexpressing ACAT1 was decreased in vivo. In addition, the migratory and invasive capacities of NPC cells was inhibited by ACAT1 overexpression. Importantly, the higher level of ACAT1 was accompanied by an increased expression of CDH1, EPCAM, and a decreased expression of vimentin and SPARC. This strongly indicates that ACAT1 is able to affect the epithelial-mesenchymal transition in NPC, thereby controlling cellular motility. In addition, we found that ACAT1 expression increases the intracellular level of β-HB. Moreover, exogenous β-HB remarkably inhibits the growth of NPC cells in a dose-dependent manner. Conclusions We have discovered that the ketone body metabolism enzyme ACAT1 is epigenetically downregulated in NPC and acts as a potential tumor suppressor in NPC. Our findings highlight the possibility of using the modulation of ketone body metabolism as effective adjuvant therapy for NPC.