Epigenetic inactivation of hydroxymethylglutaryl CoA synthase reduces ketogenesis and facilitates tumor cell motility in clear cell renal carcinoma

Han, Peipei; Wang, Yifang; Luo, Wenqi; Lu, Yunliang; Zhou, Xiaohui; Yang, Yanping; Zheng, Qian; Li, Danping; Wu, Shu; Li, Limei; Zhang, Haishan; Zhao, Jun; Zhang, Zhe; Matskova, Liudmila; Li, Ping; Zhou, Xiaoying

doi:10.1016/j.prp.2021.153622

Cited by 9 publications

(3 citation statements)

References 37 publications

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“…The upstream regulation of Hmgcs2 is associated with acetylation, methylation, transcription factors, miRNAs. 40 , 41 , 42 , 43 Nevertheless, there is extremely limited knowledge of the regulatory relationship between miRNAs and Hmgcs2. A number of miRNAs have deem demonstrated to regulate the progression of DCM.…”

Section: Discussionmentioning

confidence: 99%

Hmgcs2 is the hub gene in diabetic cardiomyopathy and is negatively regulated by Hmgcs2, promoting high glucose‐induced cardiomyocyte injury

Wang,

Ping,

Bai

et al. 2024

Immunity Inflam & Disease

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BackgroundDiabetic cardiomyopathy (DCM) represents a major cause of heart failure and a large medical burden worldwide. This study screened the potentially regulatory targets of DCM and analyzed their roles in high glucose (HG)‐induced cardiomyocyte injury.MethodsThrough GEO database, we obtained rat DCM expression chips and screened differentially expressed genes. Rat cardiomyocytes (H9C2) were induced with HG. 3‐hydroxy‐3‐methylglutarylcoenzyme A synthase 2 (Hmgcs2) and microRNA (miR)‐363‐5p expression patterns in cells were measured by real‐time quantitative polymerase chain reaction or Western blot assay, with the dual‐luciferase assay to analyze their binding relationship. Then, 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide assay, lactate dehydrogenase assay, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, enzyme‐linked immunosorbent assay, and various assay kits were applied to evaluate cell viability, cytotoxicity, apoptosis, inflammation responses, and oxidative burden.ResultsHmgcs2 was the vital hub gene in DCM. Hmgcs2 was upregulated in HG‐induced cardiomyocytes. Hmgcs2 downregulation increased cell viability, decreased TUNEL‐positive cell number, reduced HG‐induced inflammation and oxidative stress. miR‐363‐5p is the upstream miRNA of Hmgcs2. miR‐363‐5p overexpression attenuated HG‐induced cell injury.ConclusionsHmgcs2 had the most critical regulatory role in DCM. We for the first time reported that miR‐363‐5p inhibited Hmgcs2 expression, thereby alleviating HG‐induced cardiomyocyte injury.

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Section: Discussionmentioning

confidence: 99%

Hmgcs2 is the hub gene in diabetic cardiomyopathy and is negatively regulated by Hmgcs2, promoting high glucose‐induced cardiomyocyte injury

Wang,

Ping,

Bai

et al. 2024

Immunity Inflam & Disease

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“…We also evaluated the expression of mRNA for HMGCR, that is the rate controlling enzyme of the mevalonate pathway that produces cholesterol and other isoprenoids [31][32][33], as well as the expression of mRNA for HMGCS, an enzyme that catalyzes the reaction in which acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) [34,35]. This reaction comprises the second step in the mevalonate dependent isoprenoid biosynthesis pathway, where HMG-CoA is an intermediate in both cholesterol synthesis and ketogenesis [36]. Finally, we studied mRNA expression for ASMase -an enzyme responsible for catalyzing the breakdown of sphingomyelin to ceramide and phosphorylcholine Fig.…”

Section: Discussionmentioning

confidence: 99%

The Nox2-ROS-Nlrp3 Inflammasome Signaling Stimulates in the Hematopoietic Stem/Progenitor Cells Lipogenesis to Facilitate Membrane Lipid Raft Formation

Abdelbaset‐Ismail

Ciechanowicz

Bujko

et al. 2022

Stem Cell Rev and Rep

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Proliferation, metabolism, and migration of hematopoietic stem/progenitor cells (HSPCs) are coordinated by receptors expressed on outer cell membranes that are integrated into microdomains, known as membrane lipid rafts (MLRs). These structures float freely in the cell membrane bilayer and are enriched in cholesterol and sphingolipids for their functional integrity. Receptors, if expressed in MLRs, have prolonged occupancy on the cell surface and enhanced signaling power. Based on this, we have become interested in the regulation of synthesis of MLRs components in HSPCs. To address this, we tested the effect of selected factors that promote proliferation or migration and their potential involvement in the synthesis of MLRs components in HSPCs. Based on our previous research showing that HSPCs from Nox2-KO and Nlrp3-KO mice display a profound defect in MLRs formation, we focused on the role of Nox2-ROS-Nlrp3 inflammasome in regulating lipogenesis in HSPCs. We found that while at steady state conditions, Nox2-derived ROS is required for a proper expression of enzymes regulating lipogenesis, during inflammation, this effect is augmented by Nlrp3 inflammasome. Thus, our data sheds new light on the regulation of lipogenesis in HSPCs and the involvement of the Nox2-ROS-Nlrp3 inflammasome axis that differently regulates lipogenesis at steady state conditions and in response to inflammation, modulating MLRs-mediated responsiveness of these cells to external stimuli. Graphical Abstract

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“…The increase in ketones can impair cancer cell growth while maintaining the functions of healthy tissues [ 122 , 127 ]. MYC represses 3-hydroxymethylglutaryl-CoA synthase ( HMGCS2 ) in colon cancer [ 128 ] and decreased expression of HMGCS2 is found in ccRCC [ 129 ] and hepatocellular carcinoma [ 130 ], associated with worse patient outcome. Inactivation of hydroxymethylglutaryl-CoA lyase resulted in enhanced proliferation and metastasis of nasopharyngeal carcinoma [ 131 ].…”

Section: Ketogenic Diet and Mitochondriamentioning

confidence: 99%

Targeting mitochondrial metabolism for precision medicine in cancer

et al. 2022

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During decades, the research field of cancer metabolism was based on the Warburg effect, described almost one century ago. Lately, the key role of mitochondria in cancer development has been demonstrated. Many mitochondrial pathways including oxidative phosphorylation, fatty acid, glutamine, and one carbon metabolism are altered in tumors, due to mutations in oncogenes and tumor suppressor genes, as well as in metabolic enzymes. This results in metabolic reprogramming that sustains rapid cell proliferation and can lead to an increase in reactive oxygen species used by cancer cells to maintain pro-tumorigenic signaling pathways while avoiding cellular death. The knowledge acquired on the importance of mitochondrial cancer metabolism is now being translated into clinical practice. Detailed genomic, transcriptomic, and metabolomic analysis of tumors are necessary to develop more precise treatments. The successful use of drugs targeting metabolic mitochondrial enzymes has highlighted the potential for their use in precision medicine and many therapeutic candidates are in clinical trials. However, development of efficient personalized drugs has proved challenging and the combination with other strategies such as chemocytotoxic drugs, immunotherapy, and ketogenic or calorie restriction diets is likely necessary to boost their potential. In this review, we summarize the main mitochondrial features, metabolic pathways, and their alterations in different cancer types. We also present an overview of current inhibitors, highlight enzymes that are attractive targets, and discuss challenges with translation of these approaches into clinical practice. The role of mitochondria in cancer is indisputable and presents several attractive targets for both tailored and personalized cancer therapy.

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Epigenetic inactivation of hydroxymethylglutaryl CoA synthase reduces ketogenesis and facilitates tumor cell motility in clear cell renal carcinoma

Cited by 9 publications

References 37 publications

Hmgcs2 is the hub gene in diabetic cardiomyopathy and is negatively regulated by Hmgcs2, promoting high glucose‐induced cardiomyocyte injury

Hmgcs2 is the hub gene in diabetic cardiomyopathy and is negatively regulated by Hmgcs2, promoting high glucose‐induced cardiomyocyte injury

The Nox2-ROS-Nlrp3 Inflammasome Signaling Stimulates in the Hematopoietic Stem/Progenitor Cells Lipogenesis to Facilitate Membrane Lipid Raft Formation

Targeting mitochondrial metabolism for precision medicine in cancer

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