Elovl6 is a negative clinical predictor for liver cancer and knockdown of Elovl6 reduces murine liver cancer progression

Su, Yu; Yin, Feng; Wu, Hung Tsung; Huang, Yao; Tung, Chao Ling; Wu, Pensée; Chang, Chih Jen; Shiau, Ai‐Li; Wu, Chao

doi:10.1038/s41598-018-24633-3

Cited by 50 publications

(48 citation statements)

References 19 publications

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“…Elongation of very long-chain fatty acids proteins (Elovl), as rate-limiting enzymes, play a crucial role in the elongation step of LCFAs biosynthesis. Elongation of very long chain fatty acids protein 6 (Elovl6) acts to convert palmitate (C16: 0) or palmitoleic acid (C16:1 n-7) to stearate (C18:0) or vaccenic acid (C18:1 n-7) [2,3,4]. It was first discovered in mice [5].…”

Section: Introductionmentioning

confidence: 99%

Molecular Cloning, Characterization, and Nutritional Regulation of Elovl6 in Large Yellow Croaker (Larimichthys crocea)

Pang

Xiang

et al. 2019

IJMS

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Elongation of very long chain fatty acids protein 6 (Elovl6) is a key enzyme in fatty acid synthesis, which participates in converting palmitate (C16:0) to stearate (C18:0). Although studies of Elovl6 have been carried out in mammals, the nutritional regulation of elovl6 in fish remains poorly understood. In the present study, the cloning and nutritional regulation of elovl6 were determined in large yellow croaker. Sequence and phylogenetic analysis revealed that the full-length cDNA of elovl6 was 1360 bp, including an open reading frame of 810 bp encoding a putative protein of 269 amino acid that possesses the characteristic features of Elovl proteins. The transcript level of elovl6 was significantly increased in the liver of croaker fed the diets with soybean oil (enriched with 18: 2n-6, LA) or linseed oil (enriched with 18: 3n-3, ALA) than that in croaker fed the diet with fish oil (enriched with 20: 5n-3 and 22: 6n-3). Correspondingly, the elovl6 expression in croaker’s hepatocytes treated with ALA or LA was remarkably increased compared to the controls. Furthermore, the transcription factors including hepatocyte nuclear factor 1α (HNF1α), CCAAT-enhancer-binding protein β (CEBPβ), retinoid X receptor α (RXRα), and cAMP response element-binding protein 1 (CREB1) greatly enhanced promoter activity of elovl6 in large yellow croaker, and the expression of transcription factors is consistent with the changes of elovl6 expression in response to fatty acids in vivo and in vitro. In conclusion, this study revealed that elovl6 expression in large yellow croaker could be upregulated by dietary ALA or LA via the increased transcriptional expression of transcription factors including hnf1α, cebpβ, rxrα, and creb1.

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Section: Introductionmentioning

confidence: 99%

Molecular Cloning, Characterization, and Nutritional Regulation of Elovl6 in Large Yellow Croaker (Larimichthys crocea)

Pang

Xiang

et al. 2019

IJMS

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“…Tumor cells have altered proliferative and metabolic abilities compared with normal cells (12,13), and the enzymes associated with fatty acid synthesis are upregulated in tumor tissues; this increases fatty acid synthesis and provides the necessary materials and energy to facilitate rapid tumor growth (14,15). Of the associated enzymes, elongation of very long-chain fatty acids family member 6 (ELOVL6) is a highly conserved member of the endoplasmic reticulase family, which is involved in the formation of long-chain fatty acids (16,17). Previous studies have found that the ELOVL6 gene serves an important role in the development and progression of breast cancer by regulating the metabolism of intracellular lipid components (18,19).…”

Section: Introductionmentioning

confidence: 99%

Decreased expression levels of ELOVL6 indicate poor prognosis in hepatocellular carcinoma

Li¹,

Wang²,

Tang³

et al. 2019

Oncol Lett

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The present study aimed to investigate the expression of elongation of very long-chain fatty acids family member 6 (ELOVL6) in hepatocellular carcinoma (HCC) tissues, and to determine its role in the development of HCC. A total of 377 HCC specimens were collected for tissue microarray and immunohistochemistry analyses. The ELOVL6 IHC score for HCC tissues was 0.97±0.71, which was significantly lower than that of the matched adjacent normal tissues (1.32±0.68; P<0.001). Patients with low levels of ELOVL6 expression were older (P=0.014) and possessed larger sized tumors (P=0.039) than patients with high expression levels. Additionally, Kaplan-Meier analysis revealed that patients with low ELOVL6 expression levels also had significantly poorer overall (P<0.001) and disease-free (P=0.029) survival times, and a greater probability of recurrence. The tumor size, tumor-node-metastasis (TNM) stage, vascular invasion and ELOVL6 expression were all shown to be prognostic variables for overall survival in patients with HCC. Multivariate analysis revealed that vascular invasion (P<0.001), TNM stage (P<0.001) and ELOVL6 expression (P=0.001) were independent prognostic variables for overall survival. In addition, vascular invasion (P=0.032) and ELOVL6 expression (P=0.041) were independent risk factors for disease-free survival, and vascular invasion (P=0.019) and ELOVL6 expression (P=0.045) were independent risk factors associated with HCC recurrence. The present study revealed that in patients with HCC, ELOVL6 expression level was reduced in HCC tissues, and that higher ELOVL6 expression levels correlated with longer survival times. This indicates that ELOVL6 may serves as an independent marker of poor patient outcome.

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“…VPS53 , a component of the GARP complex involved in sphingolipid homeostasis, is a tumor suppressor in hepatocellular carcinoma [203–205]. Inhibition of ELOVL6 (homologous to yeast ELO2 and ELO3 ) in mice reduces tumor growth and increases survival [206]. The histone demethylase, JHD1/KDM2B , is overexpressed in pancreatic cancer [207] and is associated with poor prognosis in glioma [208] and triple negative breast cancer [209].…”

Section: Resultsmentioning

confidence: 99%

A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin

Santos

Hartman

2019

Preprint

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Background: Saccharomyces cerevisiae represses respiration in the presence of adequate glucose, mimicking the Warburg effect, termed aerobic glycolysis. We conducted yeast phenomic experiments to characterize differential doxorubicin-gene interaction, in the context of respiration vs. glycolysis. The resulting systems level biology about doxorubicin cytotoxicity, including the influence of the Warburg effect, was integrated with cancer pharmacogenomics data to identify potentially causal correlations between differential gene expression and anti-cancer efficacy. Methods: Quantitative high-throughput cell array phenotyping (Q-HTCP) was used to measure cell proliferation phenotypes (CPPs) of the yeast gene knockout/knockdown library, treated with escalating doxorubicin concentrations in fermentable and non-fermentable media. Doxorubicin-gene interaction was quantified by departure of the observed and expected phenotypes for the doxorubicin-treated mutant strain, with respect to phenotypes for the untreated mutant strain and both the treated and untreated reference strain. Recursive expectation-maximization clustering (REMc) and Gene Ontology-based analyses of interactions were used to identify functional biological modules that buffer doxorubicin cytotoxicity, and to characterize their Warburg-dependence. Yeast phenomic data was applied to cancer cell line pharmacogenomics data to predict differential gene expression that causally influences the anti-tumor efficacy, and potentially the anthracycline-associated host toxicity, of doxorubicin. Results: Doxorubicin cytotoxicity was greater with respiration, suggesting the Warburg effect can influence therapeutic efficacy. Accordingly, doxorubicin drug-gene interaction was more extensive with respiration, including increased buffering by cellular processes related to chromatin organization, protein folding and modification, translation reinitiation, spermine metabolism, and fatty acid beta-oxidation. Pathway enrichment was less notable for glycolysis-specific buffering. Cellular processes exerting influence relatively independently, with respect to Warburg status, included homologous recombination, sphingolipid homeostasis, telomere tethering at nuclear periphery, and actin cortical patch localization. Causality for differential gene expression associated with doxorubicin cytotoxicity in tumor cells was predicted within the biological context of the phenomic model. Conclusions: Warburg status influences the genetic requirements to buffer doxorubicin toxicity. Yeast phenomics provides an experimental platform to model the complexity of gene interaction networks that influence human disease phenotypes, as in this example of chemotherapy response. High-resolution, systems level yeast phenotyping is useful to predict the biological influence of functional variation on disease, offering the potential to fundamentally advance precision medicine.

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Elovl6 is a negative clinical predictor for liver cancer and knockdown of Elovl6 reduces murine liver cancer progression

Cited by 50 publications

References 19 publications

Molecular Cloning, Characterization, and Nutritional Regulation of Elovl6 in Large Yellow Croaker (Larimichthys crocea)

Molecular Cloning, Characterization, and Nutritional Regulation of Elovl6 in Large Yellow Croaker (Larimichthys crocea)

Decreased expression levels of ELOVL6 indicate poor prognosis in hepatocellular carcinoma

A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin

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