PI3K/Akt信号通路对DNA甲基转移酶3B基因表达的调控及其分子机制研究
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摘要
肿瘤细胞表现广泛而显著的表观遗传学变化,包括DNA甲基化和染色质修饰。DNA甲基化是最广为人知的表观遗传学标志,DNA甲基化主要由DNA甲基转移酶(DNA (cytosine-5)-methyltransferases, DNMTs)(EC 2.1.1.37)所控制。目前,已鉴定的人类具有催化活性的DNMTs有三种：DNMT1, DNMT3A和DNMT3B,其编码基因分别位于染色体19p13.2.、2p23和20q11.2。DNMT1优先选择DNA复制过程中所形成以半甲基化状态存在的DNA双链作为催化底物,而DNMT3A和DNMT3B是从头(de novo) DNA甲基化修饰所必须的,主要为在细胞内建立新DNA甲基化类型所必须。研究发现在肿瘤细胞中存在异常DNA甲基化类型,即广泛的DNA低甲基化与某些基因启动子特异高甲基化。发生在启动子CpG岛高甲基化可影响许多与肿瘤细胞发生发展密切相关基因的表达,在恶性肿瘤以及在癌旁组织向恶性状态转变过程中均发现DNMTs升高。有学者认为具有从头DNA甲基化作用的DNMT3B在肿瘤发生发展中具有更重要作用。在细胞内PI3K/Akt信号通路调控众多信号转导途径,例如细胞生长与存活、细胞间信息传递等。异常PI3K/Akt信号通路参与肿瘤形成与转移。我们实验室已报道PI3K/Akt信号通路可以维持DNMT1蛋白稳定性,从而在肿瘤发生中起促进作用,但PI3K/Akt信号通路对DNMT3B基因表达影响及调控尚未见报道。
在本文第一部分实验中,我们在6株人肝癌(Human hepatocellular carcinoma, HCC)细胞株中发现DNMT3B mRNA表达水平与Akt1 mRNA或Akt2 mRNA表达水平相关；不同HCC细胞株的DNMT3B3 mRNA水平与DNMT3B4 mRNA水平比值有较大的差异。此外,我们发现人肝癌组织中DNMT3B基因表达明显高于其相对应癌旁组织。
为了探讨Akt是否参与DNMT3B基因调控,在第二部分实验中,我们首先检测Akt作为上游调节剂及增量调节剂的PI3K对DNMT3B基因影响,研究发现PI3K的小分子特异性抑制剂LY294002在BEL-7404细胞株中下调DNMT3B mRNA和蛋白质水平且呈剂量效应关系和时间效应关系。我们观察到LY294002对DNMT3B mRNA表达的下调降低程度在各个时间点均高于其对DNMT3B蛋白的下调程度,提示LY294002对DNMT3B基因下调可能存在着转录水平调控。此外,我们研究发现LY294002诱导DNMT3B基因表达下调并不伴随DNMT3B亚细胞定位变化。在SMCC7721细胞株及L02细胞株均观察到LY294002降低DNMT3B基因表达。接着我们还应用蛋白质合成抑制剂CHX来检测LY294002对DNMT3B基因表达下调是否与蛋白质从头机器抑制相关,结果发现LY294002不影响DNMT3B蛋白的稳定性。在第二部分实验中,我们还利用本实验室已经建立的持续性活化Akt2的小鼠胚胎成纤维细胞株(mouse embryonic fibroblasts, MEFs)及稳定转染Akt1/2 shRNA的BEL-7404细胞株去研究Akt对DNMT3B基因调控作用,发现Akt2持续性活化导致DNMT3B mRNA及蛋白质水平升高,而在BEL-7404细胞中敲低Aktl／2引起DNMT3B mRNA及蛋白质水平均降低。再者,我们观察到Akt下游信息分子糖原合酶激酶-3β(glycogen synthase kinase-3p, GSK-3β)抑制剂氯化锂可促进DNMT3B基因表达中度增加。以上实验结果表明DNMT3B基因表达受到PI3K／Akt信号通路的调控。
为了深入阐明PI3K/Akt信号通路调控DNMT3B基因表达的分子机制,.在第三部分实验中,我们研究了LY294002对DNMT3B启动子活性的影响。首先我们依据Yanagisawa报道,构建了四个不同长度DNMT3B启动子片段,包括核心启动子序列及基本启动子序列,并将它们克隆到pGL3-Basic荧光素酶报告基因上游,经测序比对正确后,选择构建成功载体进行下一步试验。我们通过瞬时转染方法及双荧光素酶检测系统研究启动子质粒在BEL-7404细胞中的表达情况,发现核心启动子序列表达荧光素酶活性最高,结果与文献报道中基本相同。接着我们观察了LY294002对这四种DNMT3B启动子活性影响,发现荧火虫荧光素酶及作为内参的海肾荧光素酶活性均比LY294002未处理组低,因此,我们采用LY294002处理pGL3-Basic质粒(具有基本转录活性)前后相对荧光素酶活性比值作为判断标准,若低于此标准被认为启动子活性受到抑制。结果表明,LY294002抑制DNMT3B启动子活性。因此我们认为PI3K/Akt信号通路在转录水平调控了DNMT3B基因表达。在此部分中,我们还通过对DNMT3B的mRNA稳定性研究发现,LY294002可以促进DNMT3B mRNA降解,降低DNMT3B mRNA半衰期,表明LY294002对DNMT3B基因下调也存在转录后水平调控。实验中我们观察到HuR变化亦受LY294002调控,并呈现出时间效应关系,鉴于有研究报道HuR可增加DNMT3B基因稳定性,因此,我们推测HuR可能作为LY294002促进DNMT3B mRNA降解的中介物。此部分的实验结果表明PI3K/Akt信号通路可在转录及转录后水平调控DNMT3B基因表达。
综上所述,我们首次研究发现在人HCC细胞株BEL-7404中,PI3K/Akt信号通路可以下调DNMT3B基因表达,其下调机制是在转录水平和转录后水平；这一发现对我们认识PI3K/Akt信号通路和DNMT3B基因在肝癌发生机制中的作用具有重要意义。
Cancer cells show widespread and distinguished epigenetic changes when compared with their normal parental tissue, including DNA methylation and chromatin modification. DNA methylation is the best-known epigenetic marker and controlled by DNA methyltransferases (DNMTs). To date, three catalytically active DNMTs have been identified in human, DNMT1, DNMT3A, and DNMT3B, their encoding gene respectively located in 19p13.2.,2p23 and 20q11.2.. DNMT1 prefers hemimethylated DNA substrates and is therefore primarily responsible for maintenance methylation, which must occur during DNA replication. Dnmt3A and Dnmt3B are necessary for de novo methylation and for the establishment of new methylation patterns in mammalian cells. Aberrant DNA methylation in cancer cells includes global DNA hypomethylation and specific promoter hypermethylation of genes. Hypermethylation of the CpG-island promoter can affect genes involved in the development of cancer cells, and the levels of DNMTs are elevated in various malignancies and transition from a precancerous to a malignant state. There are reports about that de novo methyltransferase DNMT3B has more important role in the development of cancers. Within the cells, diverse processes are regulated by phosphatidylinositol 3 kinase (PI3K)/Akt signaling pathway including growth and survival and cell-cell communication. Abnormal PI3K/Akt activity has been linked to the formation of tumors, metastasis. In our previous study we found that phosphatidylinositol 3 kinase (PI3K)/Akt pathway stabilizes DNMT1 protein and advance the carcinogenesis. However, the relationship between PI3K/Akt pathway and DNMT3B gene expression is unknown.
In first section of our research, we found that Akts (Aktl or Akt2) transcripts are associated with the total DNMT3B transcripts in 6 human hepatocellular carcinoma (HCC) cell lines. We further found that there are various in the ratio of DNMT3B3 mRNA to DNMT3B4 mRNA of 6 HCC cell lines. In addition, we confirmed that DNMT3B protein was strongly higher expression in HCC tissues than each matched adjacent noncancerous tissues.
To explore the mechanisms of Akt on the regulation of DNMT3B gene expression, in second section of our work, we firstly assessed that PI3K, a upstream molecule of Akt, how to modulate DNMT3B gene expression, and found that LY294002, a small molecule specific inhibitor of PI3K pathway, down-regulated DNMT3B gene expression at the RNA and protein level in hepatocarcinoma cell line BEL-7404 in a dose-and time-dependent manner. We investigated that LY294002 down-regulated DNMT3B mRNA is prior to the down-regulation of DNMT3B protein after LY294002 treatment, which suggested that there was translational regulation. Moreover, we observed that down-regulation of DNMT3B gene expression by LY294002 was not accompanyed with the sub-cellular location of DNMT3B. Furthermore, down-regulation by LY294002 was also found in other two hepatocarcinoma cell lines SMCC7721 and L02. In addition, we performed a CHX chase protein decay assay between LY294002 treatment and without treatment to assesse the relationship between down-regulation of DNMT3B with LY294002 treatment and de novo synthesis of protein machinery. The result showed that LY294002 did not alter the stability of DNMT3B protein. In second section of our work, we found higher DNMT3B mRNA and protein levels in Myr-Akt2-MEFs constructed by our lab and expressed constitute activation of Akt2 than in MSCV-MEFs. Meanwhile, we found that the knockdown of Aktl and Akt2 caused the decrease of DNMT3B mRNA and protein levels in BEL-7404 stably transfected with Aktl/2 shRNA human lentiviral particles (Aktl/2 siRNA). To further confirm Akt regulate the DNMT3B gene expression, we observed Lithium chloride, an inhibitor of GSK3βwhich is a downstreamed molecule of Akt, moderately increased the DNMT3B protein in the BEL-7404 cells. All these findings suggest that PI3K/Akt modulates the DNMT3B gene expression.
In order to deeply demonstrate the mechanism of regulating DNMT3B gene expression by PI3K/Akt pathway, in the third section of our study, we assessed that how the promoter of DNMT3B was affected by LY294002. Firstly, we constructed four specific DNMT3B promoter fragments which included core promoter region and base promoter sequences according to Yanagisawa's study, and were inserted upstream of the firefly luciferase gene in the pGL3-Basic vector. Next these constructs were sequenced and aligned with GeneBank. Furthermore we assayed luciferase activities of these plasmids with transiently transfection experiments and Dual-Luciferase Reporter Assay, we found the core promoter fragment revealed the highest activity in BEL-7404 cells, the data were similar to that reported in document. Moreover we investigated that both the luciferase activities of firefly and renilla were decreased in BEL-7404 cells transiently transfected with these pGL3 plasmids under with LY294002 treatment, which were consistent with the data of cell cycle assay that represented cycle arrest of the G1 phase in BEL-7404 cell treated with LY294002. Whereas the above investigation, we took the ratio of relative luciferase activity of the pGL3-Basic (occupying base transcription activity) with LY294002 treatment or untreatment to be the criterion, and found the ratio of the DNMT3B promoter constructs were lower than the criterion. These results indicated that PI3K/Akt pathway regulates the expression of DNMT3B gene at transcription control. Furthermore, we observed that LY294002 stimulation induced the increase of DNMT3B degradation using mRNA decay analysis, which suggested that down-regulation of DNMT3B by LY294002 is also post-transcriptional control. Moreover we evaluated that the HuR expression was also modulated by LY294002 in BEL-7404 cells in a time-dependent manner. Whereas DNMT3B mRNA stabilized by HuR was reported, we hypothesized that DNMT3B was down-regulated by LY294002 via HuR decrease. Taken together, these findings in the fourth sections of our study indicated that PI3K/Akt pathway regulates the expression of DNMT3B gene at transcription and post-transcription level.
In summary, we have, for the first time, demonstrated that PI3K/Akt pathway regulates the expression of DNMT3B gene at transcriptional and post-transcriptional levels, which is particularly important to understand the effects of PI3K/Akt pathway and DNMT3B gene on hepatocarcinogenesis.
在本文第一部分实验中,我们在6株人肝癌(Human hepatocellular carcinoma, HCC)细胞株中发现DNMT3B mRNA表达水平与Akt1 mRNA或Akt2 mRNA表达水平相关；不同HCC细胞株的DNMT3B3 mRNA水平与DNMT3B4 mRNA水平比值有较大的差异。此外,我们发现人肝癌组织中DNMT3B基因表达明显高于其相对应癌旁组织。
为了探讨Akt是否参与DNMT3B基因调控,在第二部分实验中,我们首先检测Akt作为上游调节剂及增量调节剂的PI3K对DNMT3B基因影响,研究发现PI3K的小分子特异性抑制剂LY294002在BEL-7404细胞株中下调DNMT3B mRNA和蛋白质水平且呈剂量效应关系和时间效应关系。我们观察到LY294002对DNMT3B mRNA表达的下调降低程度在各个时间点均高于其对DNMT3B蛋白的下调程度,提示LY294002对DNMT3B基因下调可能存在着转录水平调控。此外,我们研究发现LY294002诱导DNMT3B基因表达下调并不伴随DNMT3B亚细胞定位变化。在SMCC7721细胞株及L02细胞株均观察到LY294002降低DNMT3B基因表达。接着我们还应用蛋白质合成抑制剂CHX来检测LY294002对DNMT3B基因表达下调是否与蛋白质从头机器抑制相关,结果发现LY294002不影响DNMT3B蛋白的稳定性。在第二部分实验中,我们还利用本实验室已经建立的持续性活化Akt2的小鼠胚胎成纤维细胞株(mouse embryonic fibroblasts, MEFs)及稳定转染Akt1/2 shRNA的BEL-7404细胞株去研究Akt对DNMT3B基因调控作用,发现Akt2持续性活化导致DNMT3B mRNA及蛋白质水平升高,而在BEL-7404细胞中敲低Aktl／2引起DNMT3B mRNA及蛋白质水平均降低。再者,我们观察到Akt下游信息分子糖原合酶激酶-3β(glycogen synthase kinase-3p, GSK-3β)抑制剂氯化锂可促进DNMT3B基因表达中度增加。以上实验结果表明DNMT3B基因表达受到PI3K／Akt信号通路的调控。
为了深入阐明PI3K/Akt信号通路调控DNMT3B基因表达的分子机制,.在第三部分实验中,我们研究了LY294002对DNMT3B启动子活性的影响。首先我们依据Yanagisawa报道,构建了四个不同长度DNMT3B启动子片段,包括核心启动子序列及基本启动子序列,并将它们克隆到pGL3-Basic荧光素酶报告基因上游,经测序比对正确后,选择构建成功载体进行下一步试验。我们通过瞬时转染方法及双荧光素酶检测系统研究启动子质粒在BEL-7404细胞中的表达情况,发现核心启动子序列表达荧光素酶活性最高,结果与文献报道中基本相同。接着我们观察了LY294002对这四种DNMT3B启动子活性影响,发现荧火虫荧光素酶及作为内参的海肾荧光素酶活性均比LY294002未处理组低,因此,我们采用LY294002处理pGL3-Basic质粒(具有基本转录活性)前后相对荧光素酶活性比值作为判断标准,若低于此标准被认为启动子活性受到抑制。结果表明,LY294002抑制DNMT3B启动子活性。因此我们认为PI3K/Akt信号通路在转录水平调控了DNMT3B基因表达。在此部分中,我们还通过对DNMT3B的mRNA稳定性研究发现,LY294002可以促进DNMT3B mRNA降解,降低DNMT3B mRNA半衰期,表明LY294002对DNMT3B基因下调也存在转录后水平调控。实验中我们观察到HuR变化亦受LY294002调控,并呈现出时间效应关系,鉴于有研究报道HuR可增加DNMT3B基因稳定性,因此,我们推测HuR可能作为LY294002促进DNMT3B mRNA降解的中介物。此部分的实验结果表明PI3K/Akt信号通路可在转录及转录后水平调控DNMT3B基因表达。
综上所述,我们首次研究发现在人HCC细胞株BEL-7404中,PI3K/Akt信号通路可以下调DNMT3B基因表达,其下调机制是在转录水平和转录后水平；这一发现对我们认识PI3K/Akt信号通路和DNMT3B基因在肝癌发生机制中的作用具有重要意义。
Cancer cells show widespread and distinguished epigenetic changes when compared with their normal parental tissue, including DNA methylation and chromatin modification. DNA methylation is the best-known epigenetic marker and controlled by DNA methyltransferases (DNMTs). To date, three catalytically active DNMTs have been identified in human, DNMT1, DNMT3A, and DNMT3B, their encoding gene respectively located in 19p13.2.,2p23 and 20q11.2.. DNMT1 prefers hemimethylated DNA substrates and is therefore primarily responsible for maintenance methylation, which must occur during DNA replication. Dnmt3A and Dnmt3B are necessary for de novo methylation and for the establishment of new methylation patterns in mammalian cells. Aberrant DNA methylation in cancer cells includes global DNA hypomethylation and specific promoter hypermethylation of genes. Hypermethylation of the CpG-island promoter can affect genes involved in the development of cancer cells, and the levels of DNMTs are elevated in various malignancies and transition from a precancerous to a malignant state. There are reports about that de novo methyltransferase DNMT3B has more important role in the development of cancers. Within the cells, diverse processes are regulated by phosphatidylinositol 3 kinase (PI3K)/Akt signaling pathway including growth and survival and cell-cell communication. Abnormal PI3K/Akt activity has been linked to the formation of tumors, metastasis. In our previous study we found that phosphatidylinositol 3 kinase (PI3K)/Akt pathway stabilizes DNMT1 protein and advance the carcinogenesis. However, the relationship between PI3K/Akt pathway and DNMT3B gene expression is unknown.
In first section of our research, we found that Akts (Aktl or Akt2) transcripts are associated with the total DNMT3B transcripts in 6 human hepatocellular carcinoma (HCC) cell lines. We further found that there are various in the ratio of DNMT3B3 mRNA to DNMT3B4 mRNA of 6 HCC cell lines. In addition, we confirmed that DNMT3B protein was strongly higher expression in HCC tissues than each matched adjacent noncancerous tissues.
To explore the mechanisms of Akt on the regulation of DNMT3B gene expression, in second section of our work, we firstly assessed that PI3K, a upstream molecule of Akt, how to modulate DNMT3B gene expression, and found that LY294002, a small molecule specific inhibitor of PI3K pathway, down-regulated DNMT3B gene expression at the RNA and protein level in hepatocarcinoma cell line BEL-7404 in a dose-and time-dependent manner. We investigated that LY294002 down-regulated DNMT3B mRNA is prior to the down-regulation of DNMT3B protein after LY294002 treatment, which suggested that there was translational regulation. Moreover, we observed that down-regulation of DNMT3B gene expression by LY294002 was not accompanyed with the sub-cellular location of DNMT3B. Furthermore, down-regulation by LY294002 was also found in other two hepatocarcinoma cell lines SMCC7721 and L02. In addition, we performed a CHX chase protein decay assay between LY294002 treatment and without treatment to assesse the relationship between down-regulation of DNMT3B with LY294002 treatment and de novo synthesis of protein machinery. The result showed that LY294002 did not alter the stability of DNMT3B protein. In second section of our work, we found higher DNMT3B mRNA and protein levels in Myr-Akt2-MEFs constructed by our lab and expressed constitute activation of Akt2 than in MSCV-MEFs. Meanwhile, we found that the knockdown of Aktl and Akt2 caused the decrease of DNMT3B mRNA and protein levels in BEL-7404 stably transfected with Aktl/2 shRNA human lentiviral particles (Aktl/2 siRNA). To further confirm Akt regulate the DNMT3B gene expression, we observed Lithium chloride, an inhibitor of GSK3βwhich is a downstreamed molecule of Akt, moderately increased the DNMT3B protein in the BEL-7404 cells. All these findings suggest that PI3K/Akt modulates the DNMT3B gene expression.
In order to deeply demonstrate the mechanism of regulating DNMT3B gene expression by PI3K/Akt pathway, in the third section of our study, we assessed that how the promoter of DNMT3B was affected by LY294002. Firstly, we constructed four specific DNMT3B promoter fragments which included core promoter region and base promoter sequences according to Yanagisawa's study, and were inserted upstream of the firefly luciferase gene in the pGL3-Basic vector. Next these constructs were sequenced and aligned with GeneBank. Furthermore we assayed luciferase activities of these plasmids with transiently transfection experiments and Dual-Luciferase Reporter Assay, we found the core promoter fragment revealed the highest activity in BEL-7404 cells, the data were similar to that reported in document. Moreover we investigated that both the luciferase activities of firefly and renilla were decreased in BEL-7404 cells transiently transfected with these pGL3 plasmids under with LY294002 treatment, which were consistent with the data of cell cycle assay that represented cycle arrest of the G1 phase in BEL-7404 cell treated with LY294002. Whereas the above investigation, we took the ratio of relative luciferase activity of the pGL3-Basic (occupying base transcription activity) with LY294002 treatment or untreatment to be the criterion, and found the ratio of the DNMT3B promoter constructs were lower than the criterion. These results indicated that PI3K/Akt pathway regulates the expression of DNMT3B gene at transcription control. Furthermore, we observed that LY294002 stimulation induced the increase of DNMT3B degradation using mRNA decay analysis, which suggested that down-regulation of DNMT3B by LY294002 is also post-transcriptional control. Moreover we evaluated that the HuR expression was also modulated by LY294002 in BEL-7404 cells in a time-dependent manner. Whereas DNMT3B mRNA stabilized by HuR was reported, we hypothesized that DNMT3B was down-regulated by LY294002 via HuR decrease. Taken together, these findings in the fourth sections of our study indicated that PI3K/Akt pathway regulates the expression of DNMT3B gene at transcription and post-transcription level.
In summary, we have, for the first time, demonstrated that PI3K/Akt pathway regulates the expression of DNMT3B gene at transcriptional and post-transcriptional levels, which is particularly important to understand the effects of PI3K/Akt pathway and DNMT3B gene on hepatocarcinogenesis.
引文
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