The role of enhancer of zeste homolog 2: From viral epigenetics to the carcinogenesis of hepatocellular carcinoma

Sanna, Luca; Marchesi, Irene; Melone, Mariarosa Anna Beatrice; Bagella, Luigi

doi:10.1002/jcp.26545

Cited by 19 publications

(18 citation statements)

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“…Further studies are needed to determine the extent to which the higher expression of such liver disease-protective genes in female liver contributes to sex-differences in liver fibrosis and liver disease. Studies such as these take on added significance, given efforts to use Ezh2 inhibitors for treatment of HCC [73].…”

Section: Discussionmentioning

confidence: 99%

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Lau-Corona

Bae

Hennighausen

et al. 2019

Preprint

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31Background: Sex differences in the incidence and progression of many liver diseases, including liver 32 fibrosis and hepatocellular carcinoma, are associated with sex-biased expression of hundreds of 33 genes in the liver. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary 34 growth hormone secretion, which controls a transcriptional regulatory network operative in the context 35 of sex-biased chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive 36 chromatin mark that is specifically deposited by polycomb repressive complex-2, via its homologous 37 catalytic subunits Ezh1 and Ezh2, at many strongly female-biased genes in male mouse liver, but not 38 at male-biased genes in female liver. Results: We used Ezh1-knockout mice with a hepatocyte-39 specific knockout of Ezh2 to elucidate the sex bias of liver H3K27-trimethylation and its functional role 40 in regulating sex-differences in the liver. Combined hepatic Ezh1/Ezh2 deficiency led to a significant 41 loss of sex-biased gene expression, particularly in male liver, where many female-biased genes 42 increased in expression while male-biased genes showed decreased expression. The associated loss 43 of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also 44 more pronounced in male liver. Many genes linked to liver fibrosis and hepatocellular carcinoma were 45 induced in Ezh1/Ezh2-deficient livers, which may contribute to the increased sensitivity of these mice 46 to hepatotoxin-induced liver pathology. Conclusions: Ezh1/Ezh2-catalyzed H3K27-trimethyation is 47 thus essential for the sex-dependent epigenetic regulation of liver chromatin states controlling 48 phenotypic sex differences in liver metabolism and liver fibrosis, and may be a critical determinant of 49 the sex-bias in liver disease susceptibility. Background 52Liver disease shows marked sex differences. Hepatocellular carcinoma incidence and mortality is 53 three times higher in men than in women [1, 2], and male mice are more susceptible to chemical-54 induced hepatic carcinogenesis [3]. Males are also more susceptible to non-alcoholic fatty liver 55 disease, non-alcoholic steatohepatitis and liver fibrosis than females [4][5][6][7][8]. Underlying these sex-biased Lau-Corona et alPage 5 3/13/19 liver. Hepatic Ezh1/Ezh2 deficiency is also shown to down regulate many male-biased genes, 106presumed as a secondary response to the disruption of female-biased gene expression. Finally, we 107show that many genes associated with liver fibrosis and liver carcinogenesis are differentially 108 responsive to the loss of Ezh1/Ezh2 in male compared to female liver, which may contribute to the 109 observed sex-differences in the incidence and progression of liver cancer. 110 111 Methods 112 Animal tissues. Livers from 7-week-old male and female Ezh1-knockout mice with a hepatocyte-113 specific knockout of Ezh2 (E1/E2-KO mice, also designated Double-knockout (DKO) in the figures 114 and tables) and their age and sex...

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Section: Discussionmentioning

confidence: 99%

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Lau-Corona

Bae

Hennighausen

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Further studies are needed to determine the extent to which the higher expression of such liver disease-protective genes in female liver contributes to sex-differences in liver fibrosis and liver disease. Studies such as these take on added significance, given efforts to utilize Ezh2 inhibitors for treatment of HCC [66].…”

Section: Plos Geneticsmentioning

confidence: 99%

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

et al. 2020

View full text Add to dashboard Cite

Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased hepatic expression of hundreds of genes. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased and growth hormone-regulated chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark deposited at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver, and is catalyzed by polycomb repressive complex-2 through its homologous catalytic subunits, Ezh1 and Ezh2. Here, we used Ezh1-knockout mice with a hepatocytespecific knockout of Ezh2 to investigate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic Ezh1/Ezh2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes were increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Further, Ezh1/Ezh2 deficiency in male liver, and to a lesser extent in female liver, led to up regulation of many genes linked to liver fibrosis and liver cancer, which may contribute to the observed liver pathologies and the increased sensitivity of these mice to hepatotoxin exposure. Thus, Ezh1/Ezh2-catalyzed H3K27-trimethyation regulates sex-dependent genetic programs in liver metabolism and liver fibrosis through its sex-dependent effects on the epigenome, and may thereby determine the sex-bias in liver disease susceptibility.

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“…Several drugs used to treat cancer focus on the topic of epigenetics, which studies the changes of chromatin and, in specific, its ability to influence gene expression (Marchesi et al, 2017; Sanna et al, 2018). Drug discovery and target selection are intricate, uncertain, and expensive processes.…”

Section: Discussionmentioning

confidence: 99%

“…With the emergence of high-throughput screening and combinatorial chemistry, the development of novel anticancer drugs increased dramatically. However, chemotherapeutic drugs often lead Several drugs used to treat cancer focus on the topic of epigenetics, which studies the changes of chromatin and, in specific, its ability to influence gene expression (Marchesi et al, 2017;Sanna et al, 2018). Drug discovery and target selection are intricate, uncertain, and expensive processes.…”

Section: Discussionmentioning

confidence: 99%

Target identification of a novel unsymmetrical 1,3,4‐oxadiazole derivative with antiproliferative properties

Lyu

Sanna

Bordoni

et al. 2020

Journal Cellular Physiology

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1,3,4‐Oxadiazole derivatives are widely used in research on antineoplastic drugs. Recently, we discovered a novel unsymmetrical 1,3,4‐oxadiazole compound with antiproliferative properties called 2j. To further investigate its possible targets and molecular mechanisms, RNA‐seq was performed and the differentially expressed genes (DEGs) were obtained after treatment. Data were analyzed using functional (Gene Ontology term) and pathway (Kyoto Encyclopedia of Genes and Genomes) enrichment of the DEGs. The hub genes were determined by the analysis of protein‐protein interaction networks. The connectivity map (CMap) information provided insight into the model action of antitumor small molecule drugs. Hub genes have been identified through function gene networks using STRING analysis. The small molecular targets obtained by CMap comparison showed that 2j is a tubulin inhibitor and it acts mainly affecting tumor cells through the cell cycle, FoxO signaling pathway, apoptotic, and p53 signaling pathways. The possible targets of 2j could be TUBA1A and TUBA4A. Molecular docking results indicated that 2j interacts at the colchicine‐binding site on tubulin.

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The role of enhancer of zeste homolog 2: From viral epigenetics to the carcinogenesis of hepatocellular carcinoma

Cited by 19 publications

References 113 publications

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Target identification of a novel unsymmetrical 1,3,4‐oxadiazole derivative with antiproliferative properties

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