&lt;b&gt;Upregulation of energy metabolism-related, p53-target TIGAR and SCO2 in HuH-7 cells with p53 mutation by geranylgeranoic acid tr&lt;/b&gt;&lt;b&gt;eatment &lt;/b&gt;

Iwao, Chieko; Shidoji, Yoshihiro

doi:10.2220/biomedres.36.371

Cited by 12 publications

(13 citation statements)

References 29 publications

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“…A deregulation in any of the main glucose metabolic processes (glycolysis, TCA cycle, or gluconeogenesis) results in dysfunction in the electron transport chain that in turn affects ATP production to mitochondrial membrane potential breakdown signifying the drop in the pool of active mitochondria. Though TIGAR and SCO2 are well involved in regulating glycolysis and oxidative phosphorylation pathways, respectively, the literature suggests they are well documented in mitochondrial respiration as well 67,69‐73 . In the present study, we found that the absence of TCF19 or p53 triggers the deregulation of TIGAR and SCO2 which causes aberrant cellular glucose homeostasis and consequently impaired mitochondrial respiration.…”

Section: Discussionmentioning

confidence: 43%

“…The involvement of SCO2 and TIGAR in mitochondrial respiration has been established in the context of metabolic stress adaptation in various cancers, including HCC. 61,[65][66][67][68][69][70][71][72][73] As these genes now were known to be regulated by TCF19/p53 complex, next in order to understand their co-regulatory function in metabolic processes, we measured lactate production, ECAR, OCR, and ATP production. We found that the lactate production increases in case of TCF19 as well as p53 knocked down stable HepG2 cells (Figure 7A) indicating dysfunctional TIGAR leads to higher rate of glycolysis.…”

Section: Regulation Of Cellular Bioenergetics By Tcf19 and P53 Indicates Their Involvement In Similar Pathwaysmentioning

confidence: 99%

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TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation

et al. 2021

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Alteration in glucose homeostasis during cancer metabolism is an important phenomenon. Though several important transcription factors have been well studied in the context of the regulation of metabolic gene expression, the role of epigenetic readers in this regard remains still elusive. Epigenetic reader protein transcription factor 19 (TCF19) has been recently identified as a novel glucose and insulin‐responsive factor that modulates histone posttranslational modifications to regulate glucose homeostasis in hepatocytes. Here we report that TCF19 interacts with a non‐histone, well‐known tumor suppressor protein 53 (p53) and co‐regulates a wide array of metabolic genes. Among these, the p53‐responsive carbohydrate metabolic genes Tp53‐induced glycolysis and apoptosis regulator (TIGAR) and Cytochrome C Oxidase assembly protein 2 (SCO2), which are the key regulators of glycolysis and oxidative phosphorylation respectively, are under direct regulation of TCF19. Remarkably, TCF19 can form different transcription activation/repression complexes which show substantial overlap with that of p53, depending on glucose‐mediated variant stress situations as obtained from IP/MS studies. Interestingly, we observed that TCF19/p53 complexes either have CBP or HDAC1 to epigenetically program the expression of TIGAR and SCO2 genes depending on short‐term high glucose or prolonged high glucose conditions. TCF19 or p53 knockdown significantly altered the cellular lactate production and led to increased extracellular acidification rate. Similarly, OCR and cellular ATP production were reduced and mitochondrial membrane potential was compromised upon depletion of TCF19 or p53. Subsequently, through RNA‐Seq analysis from patients with hepatocellular carcinoma, we observed that TCF19/p53‐mediated metabolic regulation is fundamental for sustenance of cancer cells. Together the study proposes that TCF19/p53 complexes can regulate metabolic gene expression programs responsible for mitochondrial energy homeostasis and stress adaptation.

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Section: Discussionmentioning

confidence: 43%

Section: Regulation Of Cellular Bioenergetics By Tcf19 and P53 Indicates Their Involvement In Similar Pathwaysmentioning

confidence: 99%

TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation

et al. 2021

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“…The cell death is finally detectable 6-8 h after adding GGA (19). Recently, we reported that GGA at micromolar concentrations upregulated the cellular protein levels of TP53-induced glycolysis and apoptosis regulator (TIGAR) and synthesis of cytochrome c oxidase 2 (SCO2) without their transcriptional upregulation and consequently induced a metabolic shift from aerobic glycolysis to mitochondrial respiration, as revealed by metabolomics analysis in 2 h (20). In guinea pig fibroblast-derived cell lines, GGA induced a transient increase of mitochondrial superoxide production in 15 min and dissipation of m in 2 h, and cell death became evident in 6 h (21).…”

mentioning

confidence: 98%

Unequivocal evidence for endogenous geranylgeranoic acid biosynthesized from mevalonate in mammalian cells

Shidoji

Tabata

2019

Journal of Lipid Research

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“…Iwao et al used UHPLC/TOF-MS-based metabolomics to study the underlying mechanism of its anti-HCC effect. 84 Their results showed that GGA could increase fructose 6-phosphate and spermine while decreasing fructose 1,6-diphosphate and spermidine, suggesting that GGA may shift Huh7 cells from aerobic glycolysis to mitochondrial respiration via upregulating TIGAR and SCO2 protein levels. Dehydroepiandrosterone (DHEA), a steroid secreted by the brain, gastrointestinal tract, adrenal cortex and gonads, is reported to have antiproliferative properties.…”

Section: Metabolomics In Treatment Evaluationmentioning

confidence: 97%

Deciphering hepatocellular carcinoma through metabolomics: from biomarker discovery to therapy evaluation

Guo

Tan

Wang

et al. 2018

CMAR

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Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer, with increasing prevalence worldwide. The mortality rate of HCC is similar to its incidence rate, which reflects its poor prognosis. At present, the diagnosis of HCC is still mostly dependent on invasive biopsy, imaging methods, and serum α-fetoprotein (AFP) testing. Because of the asymptomatic nature of early HCC, biopsy and imaging methods usually detect HCC at the middle–late stages. AFP has limited sensitivity and specificity, as many other nonmalignant liver diseases can also result in a very high serum level of AFP. Therefore, better biomarkers with higher sensitivity and specificity at earlier stages are greatly needed. Since metabolic reprogramming is an essential hallmark of cancer and the liver is the metabolic hub of living systems, it is useful to investigate HCC from a metabolic perspective. As a noninvasive and nondestructive approach, metabolomics provides holistic information on dynamically metabolic responses of living systems to both endogenous and exogenous factors. Therefore, it would be conducive to apply metabolomics in investigating HCC. In this review, we summarize recent metabolomic studies on HCC cellular, animal, and clinicopathologic models with attention to metabolomics as a biomarker in cancer diagnosis. Recent applications of metabolomics with respect to therapeutic and prognostic evaluation of HCC are also covered, with emphasis on the potential of treatment by drugs from natural products. In the last section, the current challenges and trends of future development of metabolomics on HCC are discussed. Overall, metabolomics provides us with novel insight into the diagnosis, prognosis, and therapeutic evaluation of HCC.

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<b>Upregulation of energy metabolism-related, p53-target TIGAR and SCO2 in HuH-7 cells with p53 mutation by geranylgeranoic acid tr</b><b>eatment </b>

Cited by 12 publications

References 29 publications

TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation

TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation

Unequivocal evidence for endogenous geranylgeranoic acid biosynthesized from mevalonate in mammalian cells

Deciphering hepatocellular carcinoma through metabolomics: from biomarker discovery to therapy evaluation

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