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Epigenetic Inactivation of Acetyl-CoA Acetyltransferase 1 Promotes the Proliferation and Metastasis in Nasopharyngeal Carcinoma by Blocking Ketogenesis

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...

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Autores principales: Lu, Yunliang, Zhou, Xiaohui, Zhao, Weilin, Liao, Zhipeng, Li, Bo, Han, Peipei, Yang, Yanping, Zhong, Xuemin, Mo, Yingxi, Li, Ping, Huang, Guangwu, Xiao, Xue, Zhang, Zhe, Zhou, Xiaoying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415477/
https://www.ncbi.nlm.nih.gov/pubmed/34485115
http://dx.doi.org/10.3389/fonc.2021.667673
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author Lu, Yunliang
Zhou, Xiaohui
Zhao, Weilin
Liao, Zhipeng
Li, Bo
Han, Peipei
Yang, Yanping
Zhong, Xuemin
Mo, Yingxi
Li, Ping
Huang, Guangwu
Xiao, Xue
Zhang, Zhe
Zhou, Xiaoying
author_facet Lu, Yunliang
Zhou, Xiaohui
Zhao, Weilin
Liao, Zhipeng
Li, Bo
Han, Peipei
Yang, Yanping
Zhong, Xuemin
Mo, Yingxi
Li, Ping
Huang, Guangwu
Xiao, Xue
Zhang, Zhe
Zhou, Xiaoying
author_sort Lu, Yunliang
collection PubMed
description 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.
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spelling pubmed-84154772021-09-04 Epigenetic Inactivation of Acetyl-CoA Acetyltransferase 1 Promotes the Proliferation and Metastasis in Nasopharyngeal Carcinoma by Blocking Ketogenesis Lu, Yunliang Zhou, Xiaohui Zhao, Weilin Liao, Zhipeng Li, Bo Han, Peipei Yang, Yanping Zhong, Xuemin Mo, Yingxi Li, Ping Huang, Guangwu Xiao, Xue Zhang, Zhe Zhou, Xiaoying Front Oncol Oncology 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. Frontiers Media S.A. 2021-08-16 /pmc/articles/PMC8415477/ /pubmed/34485115 http://dx.doi.org/10.3389/fonc.2021.667673 Text en Copyright © 2021 Lu, Zhou, Zhao, Liao, Li, Han, Yang, Zhong, Mo, Li, Huang, Xiao, Zhang and Zhou https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Lu, Yunliang
Zhou, Xiaohui
Zhao, Weilin
Liao, Zhipeng
Li, Bo
Han, Peipei
Yang, Yanping
Zhong, Xuemin
Mo, Yingxi
Li, Ping
Huang, Guangwu
Xiao, Xue
Zhang, Zhe
Zhou, Xiaoying
Epigenetic Inactivation of Acetyl-CoA Acetyltransferase 1 Promotes the Proliferation and Metastasis in Nasopharyngeal Carcinoma by Blocking Ketogenesis
title Epigenetic Inactivation of Acetyl-CoA Acetyltransferase 1 Promotes the Proliferation and Metastasis in Nasopharyngeal Carcinoma by Blocking Ketogenesis
title_full Epigenetic Inactivation of Acetyl-CoA Acetyltransferase 1 Promotes the Proliferation and Metastasis in Nasopharyngeal Carcinoma by Blocking Ketogenesis
title_fullStr Epigenetic Inactivation of Acetyl-CoA Acetyltransferase 1 Promotes the Proliferation and Metastasis in Nasopharyngeal Carcinoma by Blocking Ketogenesis
title_full_unstemmed Epigenetic Inactivation of Acetyl-CoA Acetyltransferase 1 Promotes the Proliferation and Metastasis in Nasopharyngeal Carcinoma by Blocking Ketogenesis
title_short Epigenetic Inactivation of Acetyl-CoA Acetyltransferase 1 Promotes the Proliferation and Metastasis in Nasopharyngeal Carcinoma by Blocking Ketogenesis
title_sort epigenetic inactivation of acetyl-coa acetyltransferase 1 promotes the proliferation and metastasis in nasopharyngeal carcinoma by blocking ketogenesis
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415477/
https://www.ncbi.nlm.nih.gov/pubmed/34485115
http://dx.doi.org/10.3389/fonc.2021.667673
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