| DNMT3a plays a role in switches between doxorubicin-induced senescence and apoptosis of colorectal cancer cells. | |
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MedLine Citation:
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PMID: 20473858 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The DNA-damaging drug doxorubicin (Dox) induces cell senescence at concentrations significantly lower than those required for induction of apoptosis. At low Dox concentrations, tumor suppressor p53 is activated, which enhances the expression of p21(Waf1/Cip1) (p21). At high concentrations, Dox activates p53 leading to apoptosis without enhancing p21 expression. The underlying mechanisms and factors that govern the differential effects of Dox in inducing senescence and apoptosis are unclear. Here, we report that the DNA methyltransferase (DNMT) DNMT3a was upregulated by Dox especially at concentrations that induced apoptosis in HCT116 colorectal cancer cells, and this process was regulated by p53. Meanwhile, p21 expression was significantly upregulated at senescence-inducing concentrations and kept low on treatment with apoptosis-inducing concentrations of Dox. The differential expression of DNMT3a and p21 in response to Dox suggests that DNMT3a may be a key factor in switches between Dox-induced senescence and apoptosis. Moreover, when DNMT3a was silenced, treatment of HCT116 cells with apoptosis-inducing concentration of Dox increased the percentage of cells undergoing senescence, accompanied by upregulation of p21. Contrarily, senescence-inducing concentration of Dox promoted apoptosis rate, and p21 expression was repressed. Surprisingly, no changes in DNA methylation status at p21 promoter were detected at either ranges of Dox, although DNMT3a and HDAC1 were recruited to p21 promoter at apoptosis-inducing Dox concentration, where they were present in the same complex. Overall, these data demonstrate that DNMT3a impacts the expression of p21 and plays a role in determining the Dox-induced senescence and apoptosis in HCT116 cells. |
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Authors:
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Yu Zhang; Yanyan Gao; Guoping Zhang; Shuyan Huang; Zhixiong Dong; Chenfei Kong; Dongmei Su; Juan Du; Shan Zhu; Qian Liang; Jianchao Zhang; Jun Lu; Baiqu Huang |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: International journal of cancer. Journal international du cancer Volume: 128 ISSN: 1097-0215 ISO Abbreviation: Int. J. Cancer Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2010-11-29 Completed Date: 2011-01-14 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0042124 Medline TA: Int J Cancer Country: United States |
Other Details:
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Languages: eng Pagination: 551-61 Citation Subset: IM |
Affiliation:
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The Institute of Genetics and Cytology, The Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University, Changchun, China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects* Cell Aging / drug effects* Cell Line, Tumor Colorectal Neoplasms / enzymology, genetics, pathology* DNA (Cytosine-5-)-Methyltransferase / genetics*, metabolism DNA Primers Doxorubicin / pharmacology* Humans In Situ Nick-End Labeling Plasmids Reverse Transcriptase Polymerase Chain Reaction Transfection Up-Regulation |
| Chemical | |
Reg. No./Substance:
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0/DNA Primers; 23214-92-8/Doxorubicin; EC 2.1.1.37/DNA (Cytosine-5-)-Methyltransferase; EC 2.1.1.37/DNA methyltransferase 3A |
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