<i>UBE2D1</i> RNA Expression Was an Independent Unfavorable Prognostic Indicator in Lung Adenocarcinoma, but Not in Lung Squamous Cell Carcinoma

Hou, Liyan; Li, Yingbo; Wang, Ying; Xu, Dong; Cui, Hailing; Xu, Xiaoyan; Cong, Ying; Yu, Chengyong

doi:10.1155/2018/4108919

Cited by 20 publications

(15 citation statements)

References 20 publications

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“…RPS6 overexpression portends reduced survival for patients with renal carcinoma [199] and hyperphosphosphorylation of Rps6 confers poor prognosis in non-small cell lung cancer [200]. Overexpression of UBE2D1 is associated with decreased survival in lung squamous cell carcinoma tissue [201], and numerous additional ubiquitin-conjugating enzyme family members were OES in analysis of individual tissues ( Additional File 11, File A ).…”

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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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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“…Specifically, PPARG counter-regulated 12 molecules that were upregulated or downregulated by LSCC ( Figure 2). The expression levels of eight LSCC markers (XIAP, UBE2D1, SKP2, ACKR3, MI21, HOXA10, STAT1, and PDPN) were significantly upregulated in LSCC patients [13][14][15][16][17][18][19][20] and were downregulated by PPARG [21][22][23][24][25][26][27][28]. On the other hand, PPARG could activate multiple genes [29][30][31][32][33] inhibited by LSCC [34][35][36][37][38], including MIR 223, PTEN, ANGPT1, CYP2A6, and FOXA2.…”

Section: Ppar Researchmentioning

confidence: 99%

“…In the LSCC diagnostic network (Figure 2), E2 ubiquitin-conjugating enzymes (UBE2D1), E3 ubiquitin ligases (XIAP), and SKP2 were involved in the regulation of protein ubiquitination. The expression of XIAP, UBE2D1, and SKP2 downregulated by PPARG at the transcriptional level [21,22,41] were [13][14][15]. PPARG may also play a role in the progression of LSCC by interfering upstream regulators of LSCC, as shown in Figure 3.…”

Section: Ppar Researchmentioning

confidence: 99%

PPARG Could Work as a Valid Therapeutic Strategy for the Treatment of Lung Squamous Cell Carcinoma

Shi¹,

Huang

et al. 2020

PPAR Research

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Previous studies showed that PPAR-gamma (PPARG) ligands might serve as potential therapeutic agents for nonsmall cell lung cancer (NSCLC). However, a few studies reported the specific relationship between PPARG and lung squamous cell carcinoma (LSCC). Here, we made an effort to explore the relationship between PPARG and LSCC. First, we used mega-analysis and partial mega-analysis to analyze the effects of PPARG on LSCC by using 12 independent LSCC expression datasets (285 healthy controls and 375 LSCC cases). Then, literature-based molecular pathways between PPARG and LSCC were established. After that, a gene set enrichment analysis (GSEA) was conducted to study the functionalities of PPARG and PPARG-driven triggers within the molecular pathways. Finally, another mega-analysis was constructed to test the expression changes of PPARG and its driven targets. The partial mega-analysis showed a significant downregulated expression of PPARG in LSCC (LFC=−1.08, p value=0.00073). Twelve diagnostic markers and four prognostic markers were identified within multiple PPARG-LSCC regulatory pathways. Our results suggested that the activation of PPARG expression may inhibit the development and progression of LSCC through the regulation of LSCC upstream regulators and downstream marker genes, which were involved in tumor cell proliferation and protein polyubiquitination/ubiquitination.

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“…Dysregulation of UBE2D is involved in carcinogenesis as it promotes ubiquitination of the p53 protein [57,58]. Accordingly, silencing UBE2Ds upregulates p53, which is associated with increased apoptosis of human lung cancer cells [59]. Moreover, UBE2D4 (also known as HBUCE1) interacts with the E3 ubiquitin ligase CHIP and modulates cell cycle activities and proliferation of cancer cells [60].…”

Section: Ube2d1 In Cancermentioning

confidence: 99%

E2 ubiquitin-conjugating enzymes in cancer: Implications for immunotherapeutic interventions

Hosseini

Okoye

Chaleshtari

et al. 2019

Clinica Chimica Acta

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Despite the medical advances of the 21st century, the incidence of cancer continues to increase and the search for a universal cure remains a major health challenge. Our lack of understanding the complex pathophysiology of the tumor microenvironment has hindered the development and efficiency of anti-cancer therapeutic strategies. The tumor microenvironment, composed of multiple cellular and non-cellular components, enables tumorpromoting processes such as proliferation, angiogenesis, migration and invasion, metastasis, and drug resistance. The ubiquitin-mediated degradation system is involved in several physiologic processes including cell cycling, signal transduction, receptor downregulation, endocytosis and transcriptional regulation. Ubiquitination includes attachment of ubiquitin to target proteins via E1 (activating), E2 (conjugating) and E3 (ligating) enzymes. Several studies have shown that E2 enzymes are dysregulated in variety of cancers. Multiple investigations have demonstrated the involvement of E2s in various tumor-promoting processes including DNA repair, cell cycle progression, apoptosis and oncogenic signaling. E2 enzymes consist of 40 members that facilitate ubiquitinsubstrate conjugation thereby modulating the stability and interaction of various proteins. As such, E2s are potential biomarkers as diagnostic, prognostic and therapeutic tools. In this review, we discuss the role of E2s in modulating various types of cancer.

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UBE2D1 RNA Expression Was an Independent Unfavorable Prognostic Indicator in Lung Adenocarcinoma, but Not in Lung Squamous Cell Carcinoma

Cited by 20 publications

References 20 publications

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

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

PPARG Could Work as a Valid Therapeutic Strategy for the Treatment of Lung Squamous Cell Carcinoma

E2 ubiquitin-conjugating enzymes in cancer: Implications for immunotherapeutic interventions

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