Abstract
The dysregulation of epigenetic modification and energy metabolism cooperatively contribute to the tumorigenesis of nasopharyngeal carcinoma (NPC). However, the detailed mechanisms underlying their joint contribution to NPC development and progression remain unclear. Here, we investigate the role of Acy1 Coenzyme A Acyltransferases1 (ACAT1), a key enzyme in the metabolic pathway of ketone bodies, in the proliferation and metastasis of NPC and to elucidate the underlying molecular mechanisms. Ketogenesis, plays a critical role in tumorigenesis. Previously, we reported two enzymes involved in ketone body metabolism mediate epigenetic silencing and act as tumor suppressor genes in NPC. Here, we identify another key enzyme, Acetyl-CoA acetyltransferase 1 (ACAT1), and show that its transcriptional inactivation in NPC is due to promoter hypermethylation. Ectopic overexpression of ACAT1 significantly suppressed the proliferation and colony formation of NPC cells in vitro. The migratory and invasive capacity of NPC cells was inhibited by ACAT1. The tumorigenesis of NPC cells overexpressing ACAT1 was decreased in vivo. Elevated ACAT1 in NPC cells was accompanied by an elevated expression of CDH1 and a reduced expression of vimentin and SPARC, strongly indicating that ACAT1 is involved in regulating epithelial-mesenchymal transition (EMT). We also found that ACAT1 contributes to increased intracellular levels of β-hydroxybutyrate (β-HB). Exogenously supplied β-HB significantly inhibits the growth of NPC cells in a dose-dependent manner. In summary, ACAT1 may function as a tumor suppressor via modulation of ketogenesis and could thus serve as a potential therapeutic target in NPC. In summary, our data suggest that regulation of ketogenesis may serve as adjuvant therapy in NPC.
Highlights
Aberrant energy metabolism was defined as one of the hallmarks of cancer [1]
We found that lipid droplets (LDs) accumulate in nasopharyngeal carcinoma (NPC), and the amount of intracellular LDs is associated with the growth and motility of NPC [11], indicating that an aberrant lipid metabolism contributes to the malignant behavior of tumor cells
To reveal the altered expression of Acetyl-CoA acetyltransferase 1 (ACAT1) in NPC, we firstly investigated the transcription of ACAT1 in seven NPC cell lines (HK1, HONE1, CNE1, 5-8F, 6-10B, and C666-1) compared with an immortalized normal nasopharyngeal epithelial cell line (NP69)
Summary
Aberrant energy metabolism was defined as one of the hallmarks of cancer [1]. The metabolic reprogramming in cancer includes the generation of additional energy, providing more substrates for biosynthesis, and rebalancing cellular redox status [2], facilitating the adaption of tumor cells to the tumor microenvironment and generating extra energy to sustain their malignant growth [3,4,5,6].Nasopharyngeal carcinoma (NPC) derives from the epithelium of the nasopharynx. Aberrant energy metabolism was defined as one of the hallmarks of cancer [1]. The metabolic reprogramming in cancer includes the generation of additional energy, providing more substrates for biosynthesis, and rebalancing cellular redox status [2], facilitating the adaption of tumor cells to the tumor microenvironment and generating extra energy to sustain their malignant growth [3,4,5,6]. Nasopharyngeal carcinoma (NPC) derives from the epithelium of the nasopharynx. It is the most common one of the head and neck cancers prevalent in southern China and Southeast Asia [7]. The intensity-modulated radiotherapy (IMRT) has improved the disease control of NPC but local recurrence and distant metastasis remain therapeutic challenges [10]. Further insights into the carcinogenesis of NPC are necessary to develop new therapeutic approaches
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