Dysregulation of Ketone Body Metabolism Is Associated With Poor Prognosis for Clear Cell Renal Cell Carcinoma Patients

Cui, Wanmeng; Luo, Wenqi; Zhou, Xiaohui; Lu, Yunliang; Xu, Wenqing; Zhong, Suhua; Feng, Guosheng; Liang, Yushan; Liang, Li; Mo, Yuchang; Xiao, Xue; Huang, Guangwu; Matskova, Liudmila; Zhang, Zhe; Li, Ping; Zhou, Xiaoying

doi:10.3389/fonc.2019.01422

Cited by 20 publications

(15 citation statements)

References 46 publications

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“…Notably, the preclinical studies demonstrate that a ketogenic diet increases the radiation sensitivity in xenograft models of pancreatic cancer (36). Our previous and present findings show that overexpressing the ketogenesis genes HMGCL and ACAT1, resulted in increased intracellular b-HB in both renal cell carcinoma and NPC (13,16) genes, ketogenic diets or ketone supplementation might be a promising therapeutic approach for NPC patients. This is worthy of further confirmation in animal models.…”

Section: Discussionsupporting

confidence: 50%

“…The expression of ACAT1 was found to be decreased in clear cell renal cell carcinoma (ccRCC) (15). Restoring its expression significantly reduced the malignant behavior of ccRCC cells in vitro (16), suggesting that ACAT1 might be a tumor suppressor. On the contrary, ACAT1 was elevated in aggressive prostate cancer and was used as an effective diagnostic and prognostic biomarker (17,18).…”

Section: Introductionmentioning

confidence: 99%

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

Zhou

Zhao

et al. 2021

Front. Oncol.

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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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Section: Discussionsupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

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

Zhou

Zhao

et al. 2021

Front. Oncol.

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“…Acyl-CoA cholesterol acyltransferase1 (ACAT1/SOAT1) catalyzes the transfer of acyl groups from acyl-CoA to cholesterol to produce cholesterol ester, which is the main form of cholesterol when stored in cells and transported in plasma ( 95 ) ( Figure 2 ). A study has shown that ACAT1 mRNA and protein levels are decreased in ccRCC, and this transcriptional inactivation is significantly ( 84 ) associated with advanced pathological staging and short survival time of ccRCC ( 96 ). Another study that analyzed ACAT1 by weighted co-expression network analysis in ccRCC concluded that ACAT1 expression was decreased in high-grade ccRCC, and aggressive tumors were unable to obtain sufficient energy from ketolysis and fatty acid oxidation to support their growth ( 97 ).…”

Section: Abnormal Metabolism Of Fatty Acids and Cholesterolmentioning

confidence: 99%

The Uniqueness of Clear Cell Renal Cell Carcinoma: Summary of the Process and Abnormality of Glucose Metabolism and Lipid Metabolism in ccRCC

Che

et al. 2021

Front. Oncol.

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Kidney cancer is a cancer with an increasing incidence in recent years. Clear cell renal cell carcinoma (ccRCC) accounts for up to 80% of all kidney cancers. The understanding of the pathogenesis, tumor progression, and metastasis of renal carcinoma is not yet perfect. Kidney cancer has some characteristics that distinguish it from other cancers, and the metabolic aspect is the most obvious. The specificity of glucose and lipid metabolism in kidney cancer cells has also led to its being studied as a metabolic disease. As the most common type of kidney cancer, ccRCC has many characteristics that represent the specificity of kidney cancer. There are features that we are very concerned about, including the presence of lipid droplets in cells and the obesity paradox. These two points are closely related to glucose metabolism and lipid metabolism. Therefore, we hope to explore whether metabolic changes affect the occurrence and development of kidney cancer by looking for evidence of changes on expression at the genomic and protein levels in glucose metabolism and lipid metabolism in ccRCC. We begin with the representative phenomenon of abnormal cancer metabolism: the Warburg effect, through the collection of popular metabolic pathways and related genes in the last decade, as well as some research hotspots, including the role of ferroptosis and glutamine in cancer, systematically elaborated the factors affecting the incidence and metastasis of kidney cancer. This review also identifies the similarities and differences between kidney cancer and other cancers in order to lay a theoretical foundation and provide a valid hypothesis for future research.

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“…Notably, the preclinical studies demonstrate that a ketogenic diet increases the radiation sensitivity in xenograft models of pancreatic cancer (34). Our previous and present ndings show that overexpressing the ketogenesis genes HMGCL and ACAT1, resulted in increased intracellular β-HB in both renal cell carcinoma and NPC (16,19), thereby inhibiting the growth capacity of tumor cells. As well, exogenous β-HB remarkably suppresses the proliferation and metastasis of NPC cells.…”

Section: Discussionmentioning

confidence: 53%

“…The expression of ACAT1 was decreased in clear cell renal cell carcinoma (ccRCC) (15). Restoring its expression signi cantly reduces the malignant behavior of ccRCC cells in vitro (16), suggesting that ACAT1 might be a tumor suppressor. On the contrary, as an effective diagnostic and prognostic biomarker, ACAT1 was elevated in aggressive prostate cancer (17,18).…”

mentioning

confidence: 99%

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

Zhou

Zhao

et al. 2020

Preprint

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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.

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Dysregulation of Ketone Body Metabolism Is Associated With Poor Prognosis for Clear Cell Renal Cell Carcinoma Patients

Cited by 20 publications

References 46 publications

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

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

The Uniqueness of Clear Cell Renal Cell Carcinoma: Summary of the Process and Abnormality of Glucose Metabolism and Lipid Metabolism in ccRCC

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

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