HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma

Wang, Yuan Hsi; Liu, Chao Lien; Chiu, Wan‐Chun; Twu, Yuh Ching; Liao, Yi Jen

doi:10.3390/cancers11121876

Cited by 65 publications

(60 citation statements)

References 56 publications

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“…Its inactivation in hepatocellular carcinoma has been veri ed and was positively associated with ketone body production. Importantly, the ketone bodies inhibit tumor cell migration by reversing epithelialmesenchymal transition (EMT) signaling (28). Similarly, we showed that the epithelial markers (CDH1 and EPCAM) were increased in NPC cells after overexpressing ACAT1, while mesenchymal markers (vimentin and SPARC) were decreased.…”

Section: Discussionmentioning

confidence: 69%

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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Section: Discussionmentioning

confidence: 69%

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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“…Previously, we reported that HMGCS2 protein expression is significantly reduced in liver tissues from HCC patients. Moreover, the expression of HMGCS2 was negatively correlated with the pathological grade and clinical stage [ 29 ]. We found that HMGCS2 controls the proliferation and migration abilities of liver cancer cells by regulating the apoptosis, c-Myc/cyclin D1, and EMT signaling pathways and acts in a ketone-dependent manner [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the expression of HMGCS2 was negatively correlated with the pathological grade and clinical stage [ 29 ]. We found that HMGCS2 controls the proliferation and migration abilities of liver cancer cells by regulating the apoptosis, c-Myc/cyclin D1, and EMT signaling pathways and acts in a ketone-dependent manner [ 29 ]. Thus, using a KD will increase HMGCS2 expression, and thereby, enhance ketone production to inhibit tumor growth.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study found that elevated liver de novo lipogenesis plays a key role in the development of HCC [ 32 , 45 ]. Previously, we reported that HMGCS2 downregulation enhanced the proliferation and migration abilities of liver cancers [ 29 ]. With our new findings, it is possible that not only decreased ketone production but also upregulated de novo lipogenesis in HMGCS2 knockdown HCC cells enhanced tumor growth.…”

Section: Discussionmentioning

confidence: 99%

“…They found that the high-fat-diet feeding of HMGCS2-eliminated mice resulted in increased hepatic injury and inflammation and, therefore, suggested that ketogenesis may modulate nonalcoholic fatty liver disease [ 28 ]. Our group previously published that the loss of HMGCS2 enhanced the proliferation and metastasis of HCC [ 29 ]. However, the role of HMGCS2 in KD-mediated HCC metabolic treatment remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Loss of HMGCS2 Enhances Lipogenesis and Attenuates the Protective Effect of the Ketogenic Diet in Liver Cancer

Wang

Suk

Liao

2020

Cancers

Self Cite

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Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor with limited treatment. The ketogenic diet (KD) emerged as a metabolic therapy for cancer; however, the antitumor effect on HCC remains controversial. We previously reported that the ketogenesis rate-limiting enzyme, 3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), was downregulated in most patients with HCC. The knockdown of HMGCS2 enhanced the proliferation and metastasis ability of HCC cells. However, the role of HMGCS2 in affecting KD-mediated metabolic effects remains unclear. Here, we report that KD feeding upregulates HMGCS2 expression and inhibits HCC tumor growth, while a reverse correlation between tumor size and HMGCS2 expression was observed. We found that HCC cells with HMGCS2 downregulation possess altered lipid metabolism that increases fatty acid, triglyceride, and cholesterol synthesis. Under KD feeding, a higher tumor growth rate was observed in HMGCS2 knockdown tumors, which had increased lipid synthesis-related marker expression and a positive correlation between lipid quantity and tumor weight. In conclusion, these results demonstrate that the downregulation of HMGCS2 attenuates the protective effect of the KD by shifting ketone production to enhance de novo lipogenesis in HCC. Our study elucidates a new molecular mechanism underlying the crosstalk between HMGCS2 expression and the KD in cancer treatment, which provides more information for precision medicine in developing personalized treatment strategies.

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Time‐resolved transcriptomics of mouse gastric pit cells during postnatal development reveals features distinct from whole stomach development

Wei

et al. 2022

FEBS Letters

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Whole-organ transcriptomic analyses have emerged as a common method for characterizing developmental transitions in mammalian organs. However, it is unclear if all cell types in an organ follow the whole-organ defined developmental trajectory. Recently, a postnatal two-stage developmental process was described for the mouse stomach. Here, using laser capture microdissection to obtain in situ transcriptomic data, we show that mouse gastric pit cells exhibit four postnatal developmental stages. Interestingly, early stages are characterized by the up-regulation of genes associated with metabolism, a functionality not typically associated with pit cells. Hence, beyond revealing that not all constituent cells develop according to the whole-organ determined pathway, these results broaden our understanding of the pit cell phenotypic landscape during stomach development.

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HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma

Cited by 65 publications

References 56 publications

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

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

Loss of HMGCS2 Enhances Lipogenesis and Attenuates the Protective Effect of the Ketogenic Diet in Liver Cancer

Time‐resolved transcriptomics of mouse gastric pit cells during postnatal development reveals features distinct from whole stomach development

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