Promising roles of mammalian E2Fs in hepatocellular carcinoma

Zhan, Lei; Huang, Cheng; Meng, Xiao‐Ming; Song, Yang; Wu, Xiao‐Qin; Miu, Cheng Gui; Zhan, Xiang; Li, Jun

doi:10.1016/j.cellsig.2014.01.008

Cited by 78 publications

(72 citation statements)

References 76 publications

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“…Bioinformatics predicted the strong linkage between KLF6 attenuation and E2F1 activation in metastatic processes. E2F1 plays an important role in regulating development, differentiation, proliferation, cellular signal transduction, and apoptosis (9)(10)(11)(12). Certain studies reported that E2F1 disrupts a range of pathways in numerous cancers and is closely correlated with clinical parameters (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Gao

et al. 2017

Cancer Research

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The transcription factor KLF6 has an essential role in the development and metastasis of multiple human cancers. Paradoxically, KLF6 expression was found to be attenuated in primary metastatic clear cell renal cell carcinoma (ccRCC), such that it is unclear how KLF6 affects malignant progression in this setting. In this study, we demonstrate that KLF6 attenuation in renal cells is sufficient to promote E2F1-mediated epithelialmesenchymal transition and metastatic prowess. In a mouse xenograft model of human ccRCC, silencing KLF6 increased tumor cell proliferation and malignant character, whereas E2F1 silencing reversed these properties. These effects were corroborated in a metastatic model system, where we observed a greater number of pulmonary metastatic lesions formed by ccRCC cells where KLF6 was silenced and E2F1 enforced. Analysis of clinical specimens of ccRCC revealed that low levels of KLF6 and high levels of E2F1 correlated closely with ccRCC development. Overall, our results established the significance of activating the KLF6-E2F1 axis in aggressive ccRCC, defining a novel critical signaling mechanism that drives human ccRCC invasion and metastasis. Cancer Res; 77(2); 330-42. Ó2016 AACR.

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Section: Introductionmentioning

confidence: 99%

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Gao

et al. 2017

Cancer Research

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“…Interestingly, although the group of transcription factors regulated by methylation was similar, the two strains showed different preference for the transcription factors whose target genes were most enriched for altered methylation (Online Table III; significance values compare enrichment of transcription factor binding motifs in the differentially methylated subset versus enrichment across the entire genome; only those factors with significant p values, expressed as –log, are shown): for instance, BUB/bnJ had preferential targeting of E2F-4 signaling, whereas BALB/cJ showed greater regulation of Egr-1 targets. As a transcriptional repressor, 23 E2F-4 would be expected to normally inhibit cell cycle/proliferative genes, whereas the Egr-1 family has been recently implicated in cardiac pathologies including hypertrophy, 24 although the mechanisms by which these factors choose their genomic targets is incompletely understood. Previous studies had implicated histone regulation 25 in altering transcription factor targeting, but this is the first evidence, to our knowledge, that either of these transcription factors are regulated by DNA modification.…”

Section: Resultsmentioning

confidence: 99%

DNA Methylation Indicates Susceptibility to Isoproterenol-Induced Cardiac Pathology and Is Associated With Chromatin States

Chen

Orozco

Wang

et al. 2016

Circulation Research

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Rationale Only a small portion of the known heritability of cardiovascular diseases such as heart failure can be explained based on single gene mutations. Chromatin structure and regulation provide a substrate through which genetic differences in non-coding regions may impact cellular function and response to disease, but the mechanisms are unknown. Objective We conducted genome-wide measurements of DNA methylation in different strains of mice that are susceptible and resistant to isoproterenol-induced dysfunction to test the hypothesis that this epigenetic mark may play a causal role in the development of heart failure. Methods and Results BALB/cJ and BUB/BnJ mice, determined to be susceptible and resistant to isoproterenol-induced heart failure respectively, were administered the drug for 3 weeks via osmotic minipump. Reduced representational bisulfite sequencing was then used to compare the differences between the cardiac DNA methylome in the basal state between strains and then following isoproterenol treatment. Single base resolution DNA methylation measurements were obtained and revealed a bimodal distribution of methylation in the heart, enriched in lone intergenic CpGs and depleted from CpG islands around genes. Isoproterenol induced global decreases in methylation in both strains; however, the basal methylation pattern between strains shows striking differences that may be predictive of disease progression prior to environmental stress. The global correlation between promoter methylation and gene expression (as measured by microarray) was modest and revealed itself only with focused analyses of transcription start site and gene body regions (in contrast to when gene methylation was examined in toto). Modules of co-methylated genes displayed correlation with other protein-based epigenetic marks supporting the hypothesis that chromatin modifications act in a combinatorial manner to specify transcriptional phenotypes in the heart. Conclusions This study provides the first single base-resolution map of the mammalian cardiac DNA methylome and the first case-control analysis of the changes in DNA methylation with heart failure. The findings demonstrate marked genetic differences in DNA methylation that are associated with disease progression.

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“…51 The detailed information for the role of E2F family in cancer has been described in a recent review. 49 Similar to other quiescent tissues, the activity of E2F transcription factors is inhibited in quiescent livers by retinoblastoma, (Rb) protein. Among several members of E2F family, E2F2 seems to be a most important regulator of liver proliferation and timely liver regeneration after PH.…”

Section: P16/rb/e2f Pathway In Liver Proliferation After Ph and In LImentioning

confidence: 99%

“…It has been shown that E2F1 plays an overlapping role in HCC 48 and E2F2-E2F7 promote cancer. 49 E2F8 transcription factor is a unique member of the family which represses promoters without interactions with Rb. It has been shown that inactivation of both Rb and E2F8 works synergistically to trigger DNA replication.…”

Section: P16/rb/e2f Pathway In Liver Proliferation After Ph and In LImentioning

confidence: 99%

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

Timchenko

Lewis²

2014

Cancer Stud Mol Med Open J

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Liver cancer is one of the most lethal cancers. Quiescent liver expresses up to 20 tumor suppressor proteins including Rb, p53, CCAAT-Enhancer-Binding Protein (C/EBP)α, Hepatocyte Nuclear Factor (HNF4)α and p16 and it is well protected from development of liver cancer. However, the negative control of liver proliferation by these factors and other tumor suppressor genes is eliminated in liver cancer. Studies of liver regeneration after surgery and injury have provided fundamental mechanisms on how liver neutralizes tumor suppressor proteins for the time of regeneration; however, studies of liver cancer in animal models and in human samples showed several additional pathways of this neutralization. One of these additional pathways includes activation of a small subunit of the proteasome, Gankyrin. Gankyrin is dramatically increased in human hepatocellular carcinoma (HCC) and in animal models of carcinogenesis. Once activated Gankyrin triggers degradation of main tumor suppressor proteins during development of liver cancer using slightly different mechanisms. Recent studies identified mechanisms which repress Gankyrin in quiescent livers and mechanisms of activation of Gankyrin in liver cancer. These mechanisms involve a communication between Farnesoid X Receptor (FXR) signaling and chromatin remodelling proteins mediated by members of C/EBP family. It has been recently shown that C/EBPα plays a critical role in this network and that the activation of C/EBPα in cirrhotic livers with HCC inhibits cancer progression. This C/EBPα-dependent inhibition of liver cancer involves activation of a majority of tumor suppressor genes and repression of tumor initiating pathways such as β-catenin and c-myc. These recent findings provide a background for FXR-based and C/EBPα-based approaches to treat liver cancer.

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Promising roles of mammalian E2Fs in hepatocellular carcinoma

Cited by 78 publications

References 76 publications

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

DNA Methylation Indicates Susceptibility to Isoproterenol-Induced Cardiac Pathology and Is Associated With Chromatin States

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

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