HDACI染色质重塑作用在白血病发病与治疗中的研究
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摘要
遗传信息不仅由DNA 序列的基因密码决定,组蛋白的共价修饰所引起的染色质重塑同样也调控基因的转录,影响基因的表达,被称为“第二遗传密码”。组蛋白的异常去乙酰化修饰与多种肿瘤的发生发展密切相关,HDACI能通过抑制HDAC、重塑染色质、阻断由于HDAC 募集功能紊乱而导致的基因表达受抑,从而治疗癌症。HDACI 治疗肿瘤的研究已经取得一定的进展,但其抗癌谱和药理机制还有待于进一步研究,尤其在抗白血病方面的研究报道较少。
本研究首次发现组蛋白去乙酰化酶抑制剂SB 上调NB4、U937、HL-60、Kasumi-1、Jurkat 5 种白血病细胞共刺激分子CD86、CD80 及胞间黏附分子CD54,并证实HDACI 通过促进组蛋白乙酰化作用促进NF-кB和CREB 的表达,后者导致白血病细胞共刺激分子和黏附分子表达增强。上调的共刺激分子能刺激淋巴细胞的增殖,本研究结果为HDACI应用于抗肿瘤治疗又添有力证据,并反证了肿瘤细胞免疫分子表达下调、免疫逃避与异常的去乙酰化有关。
本研究证实SB 能诱导NB4 细胞凋亡,进一步做了联合药物实验研究,单独应用SB 即可诱导凋亡,SB+ATRA 联合应用呈协同作用,效果最强,SB+ As_2O_3 作用最差,呈拮抗作用,为临床合理联合用药提供了实验基础。
本文还首次使用蛋白质组学的方法,筛选出SB 诱导NB4 细胞凋亡过程中的22 种敏感蛋白,这些敏感蛋白中,有13 种已经被证实为凋亡相关蛋白,9 种蛋白还没有与凋亡相关性的报道,这些蛋白的鉴定为进一步研究HDACI诱导肿瘤细胞凋亡的机制及抗肿瘤药物靶点的筛选奠定了基础。
Chromatin remodeling is the alteration of chromatin localization and structure. It is a key step in the transcriptional activation of genes, also a significant mode of epigenetics modification. Epigenetics modification contains more precise gene message compared with genetype . Abnormal chromatin remodeling plays a key role on pathogenesis and development of malignant tumor and leukemia. A couple of adverse proteases——histone acetylases(HAT) and histone deacetylases(HDAC) are in charge of th acetylation state core histone. The enzymes act when they associate with correlate proteins called Coactior(CoA) and Corepressor(CoR) respectively. Abnormal binding of CoR and DNA may cause continuing deacetylation of the gene and thus depress gene transcription which may play key roles in carcinogenesis. Recently many compounds are found with the abilities to inhibit HDAC and a lot of studies verified their antitumor abilities such as inducing tumor cell differentiation, blocking cell cycle, apoptosis and immunomodulation. Potentializing the immunogenicity of tumor cells is a new way with great prospect.
Inducing tumor cells apoptosis refers to widespread tumor types, and studying on the mechanism will provide evidence for clinical drug development. Here we will focus these two aspects to explore the anti-tumor effects and mechanism of histone deacetylase inhibitor (HDACI). For the study of immunomodulation, we selected five cell strains as the study objects which are NB4,Kasumi-1, HL-60,U937 and Jurkat. The cells were treated with sodium butyrate(SB) at 0, 0.1,0.5,1.0,5.0mM concentrations and examined at different time points respectively. Cell viability examined by both trypan blue dye exclusion and MTT reduction method, applied dual- or mono- agent analysis of variance. We selected concentrations for cell survival rate >85% and with obvious growth suppression and time points which occur pre-, mid- and post- growth suppression for subsequent experiments. FACS was applied to detect the up-regulation of CD86, CD80 and CD54. Semiquantitative RT-PCR was used to examine the gene transcription of CD86 and found that CD86 mRNA was obviously enhanced by SB. To ensure that the enhanced gene transcription was due to the high acetylation state of core histone, We applied the AUT gel electrophoresis and found the core histone was highly acetylated by SB, which was coincided with the current reports. The acetylation of histone results in a relaxed chromatin structure and activates the transcription of CD86 by promoting the access of transcription factor. To further explore the mechanism of augmented CD86 transcription, we detected content changes of the two main subunits,p65 and p50,of NF-
κB in nucleic extraction from pre- and post- SB treated cells. The results reveals that the increases of p65 and p50 are remarkably coherent with the changes of CD86,which supports the view that NF-κB is one of the important transcription factors that take part in up-regulation of CD86 on tumor cells. However, the findings that pretreatment with Pyrrolidine dithiocarbamate(PDTC), a inhibitor of NF-κB ,could still up-regulate 33.57% than control group indicates that SB up-regulating CD86 may be partially dependent on the NF-κB signal transduction pathway. We then detected the changes of activated CREB with a pCREB detection kit and found that the pCREB obviously increased after SB administration. These results indicate that CREB may also be responsible for the up-regulation of CD86.Allogeneic mixed lymphocyte reaction found that NB4 cells treated with SB far more effectively stimulated proliferation of lymphocytes than untreated cells. This result supports that up-regulated costimulatory molecules and adhesion molecules are functional. We also observed the expression changes of CD86 in NB4 and HL-60 treated with ATRA, As2O3 and/or SB. Neither ATRA nor As2O3 can up-regulate CD86 expression along while SB combined ATRA show higher CD86 expression (P>0.05) which may indicate synergistic effect of the two compounds. In SB+ATRA+As2O3 and SB+As2O3 groups, positive percentage of CD86 were less than SB along group. These results indicate that As2O3 can partially counteract the ability of SB in up-regulating CD86 (P<0.05). Our research verified that histone deacetylase inhibitor SB can
up-regulate costimulatory molecules and adhesion molecules of acute leukemia cells in vitro. And we primarily investigated the mechanism of SB up- regulating the costimulatory molecules. One study showed HDACI can up-regulate MHC-Ⅰand MHC-Ⅱmolecules and CD40 in neuroblastoma cells. All of these indicate that HDACI can reinforce the activation of the first and second signal pathway for CTL by chromatin remodeling which may be good evidence for HDACI being used for immunotherapy in the future. On the other hand, it also argues that abnormal deacetylation takes part in down-regulation of immune molecular. Our research revealed that NF-кB and CREB are important transcriptional factors for SB up-regulating CD86 molecules on tumor cells, which will make for well understanding of the complex regulatory network in cells and also identifying the pathogenesis of immune molecules down-regulation in tumor cells. The study about combination of SB with ATRA and AS2O3 will become the basis for drug combination in the future. In the study of SB inducing apoptosis, we selected the NB4 cell strain which contains translocation of 15 and 17 chromosome. FACS was applied to detect cell cycle blockage and apoptosis rate. We compared SB and/or RA and/or As2O3 , and no significant difference was observed in the growth blockage among these groups. However, SB+RA caused greater apoptosis effect than SB along while SB+ As2O3 had the opposite results. These results indicate that RA has synergistic effect with SB while As2O3 can counteract with SB during SB inducing NB4 cells apoptosis.
In order to explore the overall and accurate mechanism of SB inducing NB4 apoptosis , we applied 2-D gel electrophoresis and 21 sensitive proteins were identified with mass-spectrum, these protein include Profilin I 、adenylate kinase 2 isoform b 、annexin I、A+U-rich element RNA binding factor、H2B histone family, member E、nuclear chloride ion channel protein、BTF3a、hsp27、transaldolase 1、TIP、FABP and so on. There are several apoptosis associated proteins, for example, transcriptional factor eIF5A and BTF3, Thioredoxin,hsp27, TIP and TCTP. Most of these proteins were firstly discovered to be sensitive during the process of SB inducing NB4 cells apoptosis. These proteins indicate correlated events take part in the apoptosis procedure and establish the basis for further analyze accurate mechanism of SB inducing NB4 cells apoptosis. cytoskeletal protein profilin 1 is sensitive to SB , indicating that SB may function on reversing tumor malignant phenotype. Several sensitive proteins(Cofilin, FABP,Thioredoxin) associated with drug fast show that SB can enhance cells’ sensitivity to apoptosis and chemotherapeutics by regulating correlated proteins. SB also alters expression of immunomodulatory proteins (eg.TIP) , which indicates the immune escape of leukemia cells correlate with deacetylation of hisone , also hints that SB can play anti-tumor effect by immunomodulation. The study about SB combined with RA and/or As2O3 inducing apoptosis on NB4 cells and proteomics study provide a significant basis for further study apoptotic mechanism and following treating APL with SB.
本研究首次发现组蛋白去乙酰化酶抑制剂SB 上调NB4、U937、HL-60、Kasumi-1、Jurkat 5 种白血病细胞共刺激分子CD86、CD80 及胞间黏附分子CD54,并证实HDACI 通过促进组蛋白乙酰化作用促进NF-кB和CREB 的表达,后者导致白血病细胞共刺激分子和黏附分子表达增强。上调的共刺激分子能刺激淋巴细胞的增殖,本研究结果为HDACI应用于抗肿瘤治疗又添有力证据,并反证了肿瘤细胞免疫分子表达下调、免疫逃避与异常的去乙酰化有关。
本研究证实SB 能诱导NB4 细胞凋亡,进一步做了联合药物实验研究,单独应用SB 即可诱导凋亡,SB+ATRA 联合应用呈协同作用,效果最强,SB+ As_2O_3 作用最差,呈拮抗作用,为临床合理联合用药提供了实验基础。
本文还首次使用蛋白质组学的方法,筛选出SB 诱导NB4 细胞凋亡过程中的22 种敏感蛋白,这些敏感蛋白中,有13 种已经被证实为凋亡相关蛋白,9 种蛋白还没有与凋亡相关性的报道,这些蛋白的鉴定为进一步研究HDACI诱导肿瘤细胞凋亡的机制及抗肿瘤药物靶点的筛选奠定了基础。
Chromatin remodeling is the alteration of chromatin localization and structure. It is a key step in the transcriptional activation of genes, also a significant mode of epigenetics modification. Epigenetics modification contains more precise gene message compared with genetype . Abnormal chromatin remodeling plays a key role on pathogenesis and development of malignant tumor and leukemia. A couple of adverse proteases——histone acetylases(HAT) and histone deacetylases(HDAC) are in charge of th acetylation state core histone. The enzymes act when they associate with correlate proteins called Coactior(CoA) and Corepressor(CoR) respectively. Abnormal binding of CoR and DNA may cause continuing deacetylation of the gene and thus depress gene transcription which may play key roles in carcinogenesis. Recently many compounds are found with the abilities to inhibit HDAC and a lot of studies verified their antitumor abilities such as inducing tumor cell differentiation, blocking cell cycle, apoptosis and immunomodulation. Potentializing the immunogenicity of tumor cells is a new way with great prospect.
Inducing tumor cells apoptosis refers to widespread tumor types, and studying on the mechanism will provide evidence for clinical drug development. Here we will focus these two aspects to explore the anti-tumor effects and mechanism of histone deacetylase inhibitor (HDACI). For the study of immunomodulation, we selected five cell strains as the study objects which are NB4,Kasumi-1, HL-60,U937 and Jurkat. The cells were treated with sodium butyrate(SB) at 0, 0.1,0.5,1.0,5.0mM concentrations and examined at different time points respectively. Cell viability examined by both trypan blue dye exclusion and MTT reduction method, applied dual- or mono- agent analysis of variance. We selected concentrations for cell survival rate >85% and with obvious growth suppression and time points which occur pre-, mid- and post- growth suppression for subsequent experiments. FACS was applied to detect the up-regulation of CD86, CD80 and CD54. Semiquantitative RT-PCR was used to examine the gene transcription of CD86 and found that CD86 mRNA was obviously enhanced by SB. To ensure that the enhanced gene transcription was due to the high acetylation state of core histone, We applied the AUT gel electrophoresis and found the core histone was highly acetylated by SB, which was coincided with the current reports. The acetylation of histone results in a relaxed chromatin structure and activates the transcription of CD86 by promoting the access of transcription factor. To further explore the mechanism of augmented CD86 transcription, we detected content changes of the two main subunits,p65 and p50,of NF-
κB in nucleic extraction from pre- and post- SB treated cells. The results reveals that the increases of p65 and p50 are remarkably coherent with the changes of CD86,which supports the view that NF-κB is one of the important transcription factors that take part in up-regulation of CD86 on tumor cells. However, the findings that pretreatment with Pyrrolidine dithiocarbamate(PDTC), a inhibitor of NF-κB ,could still up-regulate 33.57% than control group indicates that SB up-regulating CD86 may be partially dependent on the NF-κB signal transduction pathway. We then detected the changes of activated CREB with a pCREB detection kit and found that the pCREB obviously increased after SB administration. These results indicate that CREB may also be responsible for the up-regulation of CD86.Allogeneic mixed lymphocyte reaction found that NB4 cells treated with SB far more effectively stimulated proliferation of lymphocytes than untreated cells. This result supports that up-regulated costimulatory molecules and adhesion molecules are functional. We also observed the expression changes of CD86 in NB4 and HL-60 treated with ATRA, As2O3 and/or SB. Neither ATRA nor As2O3 can up-regulate CD86 expression along while SB combined ATRA show higher CD86 expression (P>0.05) which may indicate synergistic effect of the two compounds. In SB+ATRA+As2O3 and SB+As2O3 groups, positive percentage of CD86 were less than SB along group. These results indicate that As2O3 can partially counteract the ability of SB in up-regulating CD86 (P<0.05). Our research verified that histone deacetylase inhibitor SB can
up-regulate costimulatory molecules and adhesion molecules of acute leukemia cells in vitro. And we primarily investigated the mechanism of SB up- regulating the costimulatory molecules. One study showed HDACI can up-regulate MHC-Ⅰand MHC-Ⅱmolecules and CD40 in neuroblastoma cells. All of these indicate that HDACI can reinforce the activation of the first and second signal pathway for CTL by chromatin remodeling which may be good evidence for HDACI being used for immunotherapy in the future. On the other hand, it also argues that abnormal deacetylation takes part in down-regulation of immune molecular. Our research revealed that NF-кB and CREB are important transcriptional factors for SB up-regulating CD86 molecules on tumor cells, which will make for well understanding of the complex regulatory network in cells and also identifying the pathogenesis of immune molecules down-regulation in tumor cells. The study about combination of SB with ATRA and AS2O3 will become the basis for drug combination in the future. In the study of SB inducing apoptosis, we selected the NB4 cell strain which contains translocation of 15 and 17 chromosome. FACS was applied to detect cell cycle blockage and apoptosis rate. We compared SB and/or RA and/or As2O3 , and no significant difference was observed in the growth blockage among these groups. However, SB+RA caused greater apoptosis effect than SB along while SB+ As2O3 had the opposite results. These results indicate that RA has synergistic effect with SB while As2O3 can counteract with SB during SB inducing NB4 cells apoptosis.
In order to explore the overall and accurate mechanism of SB inducing NB4 apoptosis , we applied 2-D gel electrophoresis and 21 sensitive proteins were identified with mass-spectrum, these protein include Profilin I 、adenylate kinase 2 isoform b 、annexin I、A+U-rich element RNA binding factor、H2B histone family, member E、nuclear chloride ion channel protein、BTF3a、hsp27、transaldolase 1、TIP、FABP and so on. There are several apoptosis associated proteins, for example, transcriptional factor eIF5A and BTF3, Thioredoxin,hsp27, TIP and TCTP. Most of these proteins were firstly discovered to be sensitive during the process of SB inducing NB4 cells apoptosis. These proteins indicate correlated events take part in the apoptosis procedure and establish the basis for further analyze accurate mechanism of SB inducing NB4 cells apoptosis. cytoskeletal protein profilin 1 is sensitive to SB , indicating that SB may function on reversing tumor malignant phenotype. Several sensitive proteins(Cofilin, FABP,Thioredoxin) associated with drug fast show that SB can enhance cells’ sensitivity to apoptosis and chemotherapeutics by regulating correlated proteins. SB also alters expression of immunomodulatory proteins (eg.TIP) , which indicates the immune escape of leukemia cells correlate with deacetylation of hisone , also hints that SB can play anti-tumor effect by immunomodulation. The study about SB combined with RA and/or As2O3 inducing apoptosis on NB4 cells and proteomics study provide a significant basis for further study apoptotic mechanism and following treating APL with SB.
引文
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