转录因子SOX7及DNA甲基转移酶DNMT3a在结肠癌凋亡与衰老过程中的作用及机制研究
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摘要
肿瘤发生的主要事件是肿瘤细胞逃逸衰老和死亡程序而进入永生化,因此诱导肿瘤细胞重新获得衰老特性及诱导肿瘤细胞凋亡是抑制肿瘤生长和增殖的重要途径。SOX7是含有HMG domain的SOX转录因子家族成员。SOX基因是近些年来在动物中发现的一类编码转录因子的基因家族,参与多种早期胚胎发育过程。Wnt信号转导通路在胚胎发育及癌症发生等过程中发挥作用,Wnt通路在结直肠癌中异常激活,研究显示鼠SOX7能够下调β-catenin激活的Wnt通路报告基因活性。人SOX7基因在多种癌细胞系包括结肠癌SW480细胞中低表达,具体机制未见报道。DNA甲基化是肿瘤抑制基因在肿瘤中沉默的重要机制,DNA甲基化转移酶(DNMT)在胚胎发育和癌症发生过程中发挥重要作用。DNMTs在多种肿瘤中的表达明显上调,DNMTs在衰老与凋亡过程中都起到一定作用。在本文中,我们对SOX7在结肠癌中的表达及其在结肠癌抑癌中的作用以及DNMT3a在阿霉素诱导结肠癌衰老与凋亡转换中的作用及机制进行了研究。在Part I中,我们的工作显示,SOX7在结肠癌细胞及结肠癌组织中低表达,甲基化特异性PCR及亚硫酸氢盐测序实验表明,SOX7在结肠癌中的低表达受到DNA甲基化修饰的调控;Hoechest33342染色、MTT及克隆形成实验证实,过表达SOX7能促进结肠癌SW480细胞凋亡,抑制SW480细胞增殖及克隆形成;过表达SOX7能够抑制结肠癌中异常活化的Wnt通路。在Part II中,我们的工作显示,阿霉素能诱导结肠癌HCT116细胞中DNMT3a的表达,尤其是凋亡浓度阿霉素能够显著上调DNMT3a的表达,p53参与了阿霉素对DNMT3a的调控;衰老相关β-gal染色及凋亡相关TUNEL染色结果表明,DNMT3a在阿霉素诱导结肠癌HCT116细胞衰老与凋亡转换过程中起作用。干涉DNMT3a,在凋亡浓度阿霉素刺激下,p21的表达有所上升;过表达DNMT3a,在衰老浓度阿霉素刺激下,p21的表达有所下降;ChIP实验显示,衰老浓度阿霉素刺激结肠癌HCT116细胞,p21启动子组蛋白H3及H4高乙酰化,检测到p53的结合,而在凋亡浓度阿霉素刺激下,p21启动子组蛋白H3及H4低乙酰化,p53结合减少,检测到DNMT3a及HDAC1的结合;进一步的CoIP实验证实DNMT3a与HDAC1在凋亡浓度阿霉素刺激下存在于一个复合物中。我们的工作为更好地了解转录因子SOX7的功能,以及DNA甲基转移酶DNMT3a在阿霉素诱导结肠癌细胞衰老与凋亡转换中的作用机制提供了重要的实验依据。
Tumor cells escaping senescence and apoptosis is the main events of tumor development, so inducing tumor cells senescence and apoptosis is an important way to inhibit tumor growth and proliferation. The sex-determining region Y-box 7 (SOX7) is a member of high mobility group (HMG) transcription factor family, essential for embryonic development and endoderm differentiation. Deregulation of Wnt signaling pathway is a hallmark of colorectal cancer. Mouse SOX7 represses Wnt/β-catenin-stimulated transcription in HEK 293 cell line. But the mechanisms of the regulation of human SOX7 gene are unclear, and the tumor suppressive function of SOX7 in colorectal cancers needs to be validated. DNA methylation is an important mechanism to silence certain tumor suppressor genes in the development of tumor. DNMTs play important roles in embryonic and cancer development. DNMTs are highly expressed in many cancer cells and play roles in senescence and apoptosis. In this paper, we studied the role of SOX7 in inhibiting colorectal cancer cells and the role of DNMT3a in switches between doxorubicin (Dox)-induced senescence and apoptosis of colorectal cancer cells. In part I, we showed that the expression level of SOX7 mRNA was frequently down-regulated in human colorectal cancer cell lines and in primary colorectal tumor tissues, and the SOX7 silencing was partially due to the aberrant DNA methylation of the gene. Restoration of SOX7 induced colorectal cancer cell apoptosis, inhibited cell proliferation and colony formation. In addition, SOX7 efficiently suppressedβ-catenin-mediated transcriptional activity and altered the epigenetic modification of promoters of the Wnt target genes. In part II, we showed that the DNA methyltransferase 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 upon 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, though DNMT3a and HDAC1 were recruited to p21 promoter at apoptosis-inducing Dox concentration, where they were present in the same complex. Our work will help to further study the mechanism of SOX7 and DNMT3a in colorectal cancer senescence and apoptosis.
Tumor cells escaping senescence and apoptosis is the main events of tumor development, so inducing tumor cells senescence and apoptosis is an important way to inhibit tumor growth and proliferation. The sex-determining region Y-box 7 (SOX7) is a member of high mobility group (HMG) transcription factor family, essential for embryonic development and endoderm differentiation. Deregulation of Wnt signaling pathway is a hallmark of colorectal cancer. Mouse SOX7 represses Wnt/β-catenin-stimulated transcription in HEK 293 cell line. But the mechanisms of the regulation of human SOX7 gene are unclear, and the tumor suppressive function of SOX7 in colorectal cancers needs to be validated. DNA methylation is an important mechanism to silence certain tumor suppressor genes in the development of tumor. DNMTs play important roles in embryonic and cancer development. DNMTs are highly expressed in many cancer cells and play roles in senescence and apoptosis. In this paper, we studied the role of SOX7 in inhibiting colorectal cancer cells and the role of DNMT3a in switches between doxorubicin (Dox)-induced senescence and apoptosis of colorectal cancer cells. In part I, we showed that the expression level of SOX7 mRNA was frequently down-regulated in human colorectal cancer cell lines and in primary colorectal tumor tissues, and the SOX7 silencing was partially due to the aberrant DNA methylation of the gene. Restoration of SOX7 induced colorectal cancer cell apoptosis, inhibited cell proliferation and colony formation. In addition, SOX7 efficiently suppressedβ-catenin-mediated transcriptional activity and altered the epigenetic modification of promoters of the Wnt target genes. In part II, we showed that the DNA methyltransferase 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 upon 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, though DNMT3a and HDAC1 were recruited to p21 promoter at apoptosis-inducing Dox concentration, where they were present in the same complex. Our work will help to further study the mechanism of SOX7 and DNMT3a in colorectal cancer senescence and apoptosis.
引文
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