DNMT3a plays a role in switches between doxorubicin‐induced senescence and apoptosis of colorectal cancer cells
DNMT3a plays a role in switches between doxorubicin‐induced senescence and apoptosis of colorectal cancer cells
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DOI：
10.1002/ijc.25365
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发表时间：
2011-02
影响因子：
6.4
通讯作者：
Yu Zhang;Yanyan Gao;Guoping Zhang;Shuyan Huang;Zhi-xiong Dong;Chenfei Kong;D. Su;Juan Du;
中科院分区：
文献类型：
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作者：
Yu Zhang;Yanyan Gao;Guoping Zhang;Shuyan Huang;Zhi-xiong Dong;Chenfei Kong;D. Su;Juan Du;
DNA损伤药物阿霉素（Dox）在显著低于诱导细胞凋亡所需浓度的浓度下诱导细胞衰老。在低Dox浓度下，肿瘤抑制因子p53被激活，这增强了p21 Waf 1/Cip 1（p21）的表达。在高浓度下，Dox激活p53，导致细胞凋亡而不增强p21表达。Dox在诱导衰老和凋亡中的差异效应的潜在机制和因素尚不清楚。在这里，我们报告说，DNA甲基转移酶（DNMT）DNMT 3a的上调，特别是在浓度的Dox诱导HCT 116结直肠癌细胞凋亡，这一过程是由p53调节。同时，p21表达在衰老诱导浓度下显著上调，并且在用凋亡诱导浓度的Dox处理时保持低水平。DNMT 3a和p21对Dox反应的差异表达表明，DNMT 3a可能是Dox诱导的衰老和凋亡之间转换的关键因素。此外，当DNMT 3a沉默时，用凋亡诱导浓度的Dox处理HCT 116细胞增加了经历衰老的细胞的百分比，伴随着p21的上调。相反，衰老诱导浓度的Dox促进凋亡率，并且p21表达被抑制。令人惊讶的是，在Dox的任一范围内均未检测到p21启动子处的DNA甲基化状态的变化，尽管DNMT 3a和HDAC 1在细胞凋亡诱导Dox浓度下被募集到p21启动子，其中它们存在于相同的复合物中。总之，这些数据表明，DNMT 3a影响p21的表达，并在决定HCT 116细胞中Dox诱导的衰老和凋亡中起作用。
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 p21Waf1/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.