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Epigenetic events in liver cancer resulting from alcoholic liver disease.

French SW - Alcohol Res (2013)

Bottom Line: Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation.Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC.Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Harbor UCLA Medical Center, Torrance, California, USA.

ABSTRACT
Epigenetic mechanisms play an extensive role in the development of liver cancer (i.e., hepatocellular carcinoma [HCC]) associated with alcoholic liver disease (ALD) as well as in liver disease associated with other conditions. For example, epigenetic mechanisms, such as changes in the methylation and/or acetylation pattern of certain DNA regions or of the histone proteins around which the DNA is wrapped, contribute to the reversion of normal liver cells into progenitor and stem cells that can develop into HCC. Chronic exposure to beverage alcohol (i.e., ethanol) can induce all of these epigenetic changes. Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation. Alcohol exposure also can alter histone acetylation/deacetylation and methylation patterns through a variety of mechanisms and signaling pathways. Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC. Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD.

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These images show a double-immunostained liver biopsy from a patient with alcoholic hepatitis where most of the hepatocytes had formed Mallory-Denk bodies (MDBs). The MDBs stained positive for (A) pEZHZ (green), (B) ubiquitin (red), and (C) merged (yellow), indicating that the pEZH2 colocalized in the MDBs. Magnification ×350.
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f3-arcr-35-1-57: These images show a double-immunostained liver biopsy from a patient with alcoholic hepatitis where most of the hepatocytes had formed Mallory-Denk bodies (MDBs). The MDBs stained positive for (A) pEZHZ (green), (B) ubiquitin (red), and (C) merged (yellow), indicating that the pEZH2 colocalized in the MDBs. Magnification ×350.

Mentions: The gene-silencing pathway mediated by H3K27 methylation is linked to the second major silencing pathway (i.e., DNA methylation) via a deacetylase called SIRT 1 that is recruited by the PRC2 complex and contributes to gene silencing (Muntean and Hess 2009). SIRT 1 levels are increased in the alcohol intragastric tube-feeding rat model cited above. In contrast, when SIRT 1 activity is decreased, EZH2 levels increase, which enhances the EZH2-mediated repression of target genes (Lu et al. 2011). Upregulation of EZH2 expression in tumors appears to correlate with disease progression by maintaining a stem cell-like phenotype. Overexpression of EZH2 can lead to cancer progression mediated by deregulation of epigenetic mechanisms (Muntean and Hess 2009). However, EZH2 levels do not seem to be affected by alcohol and other factors that can induce liver damage. For example, EZH2 levels were not changed in mice that exhibited a precursor stage to HCC (as characterized by the presence of balloon cells and MDBs) after drug treatment, in liver biopsies of patients with alcoholic hepatitis, or in MDB-forming HCCs (French et al. 2012) (see figure 3). However, in all three cases there were increases in a modified form of EZH2 (i.e., phosphorylated EZH2 [pEZH2]), which is degraded more rapidly in the cells than unmodified EZH2 and is located in the MDBs as demonstrated by immunohisto-chemistry. This degradation of pEZH2 occurs at cell components called proteasomes. However, proteasomes are inhibited by ethanol excess; as a result, pEZH2 levels are increased in MDBs. Moreover, in all three cases, the levels of H3K27me3 were reduced in the nuclei of the damaged liver cells (i.e., cells that were ballooned or formed MDBs) compared with neighboring normal liver cells as shown by different experimental approaches (Bardag-Gorce et al. 2010; French et al. 2012). Paradoxically, when tumors form, they overexpress EZH2. High expression of EZH2 in tumors is associated with poor survival (Gieni and Hendzel 2009). Thus, EZH2 overexpression represses expression of the product of a tumor suppressor gene called E cadherin that causes cells to stick to each other. Accordingly, loss of E cadherin expression by tumor cells may cause loss of cell cohesion, which would promote metastasis and thus a more unfavorable prognosis.


Epigenetic events in liver cancer resulting from alcoholic liver disease.

French SW - Alcohol Res (2013)

These images show a double-immunostained liver biopsy from a patient with alcoholic hepatitis where most of the hepatocytes had formed Mallory-Denk bodies (MDBs). The MDBs stained positive for (A) pEZHZ (green), (B) ubiquitin (red), and (C) merged (yellow), indicating that the pEZH2 colocalized in the MDBs. Magnification ×350.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3860418&req=5

f3-arcr-35-1-57: These images show a double-immunostained liver biopsy from a patient with alcoholic hepatitis where most of the hepatocytes had formed Mallory-Denk bodies (MDBs). The MDBs stained positive for (A) pEZHZ (green), (B) ubiquitin (red), and (C) merged (yellow), indicating that the pEZH2 colocalized in the MDBs. Magnification ×350.
Mentions: The gene-silencing pathway mediated by H3K27 methylation is linked to the second major silencing pathway (i.e., DNA methylation) via a deacetylase called SIRT 1 that is recruited by the PRC2 complex and contributes to gene silencing (Muntean and Hess 2009). SIRT 1 levels are increased in the alcohol intragastric tube-feeding rat model cited above. In contrast, when SIRT 1 activity is decreased, EZH2 levels increase, which enhances the EZH2-mediated repression of target genes (Lu et al. 2011). Upregulation of EZH2 expression in tumors appears to correlate with disease progression by maintaining a stem cell-like phenotype. Overexpression of EZH2 can lead to cancer progression mediated by deregulation of epigenetic mechanisms (Muntean and Hess 2009). However, EZH2 levels do not seem to be affected by alcohol and other factors that can induce liver damage. For example, EZH2 levels were not changed in mice that exhibited a precursor stage to HCC (as characterized by the presence of balloon cells and MDBs) after drug treatment, in liver biopsies of patients with alcoholic hepatitis, or in MDB-forming HCCs (French et al. 2012) (see figure 3). However, in all three cases there were increases in a modified form of EZH2 (i.e., phosphorylated EZH2 [pEZH2]), which is degraded more rapidly in the cells than unmodified EZH2 and is located in the MDBs as demonstrated by immunohisto-chemistry. This degradation of pEZH2 occurs at cell components called proteasomes. However, proteasomes are inhibited by ethanol excess; as a result, pEZH2 levels are increased in MDBs. Moreover, in all three cases, the levels of H3K27me3 were reduced in the nuclei of the damaged liver cells (i.e., cells that were ballooned or formed MDBs) compared with neighboring normal liver cells as shown by different experimental approaches (Bardag-Gorce et al. 2010; French et al. 2012). Paradoxically, when tumors form, they overexpress EZH2. High expression of EZH2 in tumors is associated with poor survival (Gieni and Hendzel 2009). Thus, EZH2 overexpression represses expression of the product of a tumor suppressor gene called E cadherin that causes cells to stick to each other. Accordingly, loss of E cadherin expression by tumor cells may cause loss of cell cohesion, which would promote metastasis and thus a more unfavorable prognosis.

Bottom Line: Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation.Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC.Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Harbor UCLA Medical Center, Torrance, California, USA.

ABSTRACT
Epigenetic mechanisms play an extensive role in the development of liver cancer (i.e., hepatocellular carcinoma [HCC]) associated with alcoholic liver disease (ALD) as well as in liver disease associated with other conditions. For example, epigenetic mechanisms, such as changes in the methylation and/or acetylation pattern of certain DNA regions or of the histone proteins around which the DNA is wrapped, contribute to the reversion of normal liver cells into progenitor and stem cells that can develop into HCC. Chronic exposure to beverage alcohol (i.e., ethanol) can induce all of these epigenetic changes. Thus, ethanol metabolism results in the formation of compounds that can cause changes in DNA methylation and interfere with other components of the normal processes regulating DNA methylation. Alcohol exposure also can alter histone acetylation/deacetylation and methylation patterns through a variety of mechanisms and signaling pathways. Alcohol also acts indirectly on another molecule called toll-like receptor 4 (TLR4) that is a key component in a crucial regulatory pathway in the cells and whose dysregulation is involved in the development of HCC. Finally, alcohol use regulates an epigenetic mechanism involving small molecules called miRNAs that control transcriptional events and the expression of genes important to ALD.

Show MeSH
Related in: MedlinePlus