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Effects of histone acetylation and DNA methylation on p21( WAF1) regulation
1Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai Second Medical School, Shanghai 200001, China. jingyuanfang@yahoo.com
Abstract:
Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play an important role in the growth arrest induced in transformed cells. Although the stability of the p21( WAF1) mRNA could be altered by different signals, cell differentiation and numerous influencing factors. However, recent studies suggest that two known mechanisms of epigenesis, i.e.gene inactivation by methylation in promoter region and changes to an inactive chromatin by histone deacetylation, seem to be the best candidate mechanisms for inactivation of p21( WAF1). To date, almost no coding region p21(WAF1) mutations have been found in tumor cells, despite extensive screening of hundreds of various tumors. Hypermethylation of the p21(WAF1) promoter region may represent an alternative mechanism by which the p21(WAF1/CIP1) gene can be inactivated. The reduction of cellular DNMT protein levels also induces a corresponding rapid increase in the cell cycle regulator p21(WAF1) protein demonstrating a regulatory link between DNMT and p21(WAF1) which is independent of methylation of DNA. Both histone hyperacetylation and hypoacetylation appear to be important in the carcinoma process, and induction of the p21(WAF1) gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis. Here, we review the influence of histone acetylation and DNA methylation on p21(WAF1) transcription, and affection of pathways or factors associated such as p 53, E2A, Sp1 as well as several histone deacetylation inhibitors.
Insights
Epigenetic silencing of the p21(WAF1) gene, via DNA methylation and histone deacetylation, is crucial in cancer. Understanding these mechanisms, including factors like p53, offers insights into cell cycle regulation and carcinogenesis prevention.
Area of Science:
- Molecular Biology
- Epigenetics
- Cancer Biology
Background:
- Cell cycle progression relies on cyclin-CDK interactions.
- p21(WAF1) is a CDK inhibitor crucial for growth arrest in transformed cells.
- Epigenetic mechanisms like DNA methylation and histone deacetylation inactivate p21(WAF1).
Purpose of the Study:
- To review the influence of histone acetylation and DNA methylation on p21(WAF1) transcription.
- To explore associated factors and pathways influencing p21(WAF1) regulation.
- To highlight the role of p21(WAF1) inactivation in carcinogenesis.
Main Methods:
- Literature review of epigenetic mechanisms affecting p21(WAF1).
- Analysis of studies on DNA methylation, histone deacetylation, and p21(WAF1) expression.
- Examination of regulatory factors including p53, E2A, Sp1, and histone deacetylation inhibitors.
Main Results:
- No significant coding region mutations of p21(WAF1) found in tumors.
- Hypermethylation of the p21(WAF1) promoter is a key inactivation mechanism.
- DNMT levels inversely correlate with p21(WAF1) protein, independent of DNA methylation.
- Histone hyperacetylation can induce p21(WAF1) expression, potentially preventing cancer.
Conclusions:
- Epigenetic modifications, specifically DNA methylation and histone deacetylation, are critical for p21(WAF1) gene silencing.
- Understanding these epigenetic alterations and associated factors is vital for cancer research and therapeutic strategies.
- p21(WAF1) regulation by epigenetic mechanisms offers potential targets for cancer prevention and treatment.