表观遗传修饰在HOXB13基因转录中的调控机制及意义
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摘要
HOXB13作为一个homeodomain蛋白对前列腺癌细胞生长停滞起着重要的作用。它仅仅在AR(androgen receptor)阳性的前列腺细胞中表达,但是,具体的机制未见报道。本文探讨了表观遗传修饰对HOXB13基因转录的影响,并且对其可能的机制和意义做了深入的研究。我们证实了在AR阴性的前列腺癌中组蛋白去乙酰化酶抑制剂NaB能够诱导细胞的生长停滞并且增强HOXB13基因的表达水平。我们的研究表明组蛋白去乙酰化酶HDAC4和转录因子YY1能够在mRNA和蛋白水平上调控HOXB13基因。组蛋白去乙酰化酶HDAC4和转录因子YY1都能够以组蛋白乙酰化的表观修饰机制阻遏HOXB13基因的表达。免疫共沉淀(CoIP)实验表明转录因子YY1和组蛋白去乙酰化酶HDAC4能够存在于同一复合物中。染色质免疫沉淀(ChIP)揭示组蛋白去乙酰化酶HDAC4是由转录因子YY1招募到HOXB13基因启动子处的。启动子截短突变和点突变结果都显示HOXB13基因启动子上两个近端的YY1结合位点对YY1和HDAC4的招募起着重要的作用。MTT细胞增殖检测结果显示YY1和HDAC4能够通过抑制HOXB13基因的表达影响前列腺癌细胞的生长。我们还发现EZH2siRNA和BMI1siRNA通过部分抑制Polycomb复合物亚基EZH2和BMI1的表达进而明显提高了AR阴性的前列腺癌细胞中的HOXB13 mRNA和蛋白表达水平,ChIP分析显示在这个过程中H3K27me3起着重要的作用。DNA甲基转移酶抑制剂5-aza-dC能够诱导HOXB13 mRNA和蛋白的表达,亚硫酸氢钠测序(bisulfite genomic sequencing)的研究表明AR阴性的前列腺癌细胞中HOXB13基因启动子处的CpG岛是高甲基化的状态。DNMT3b能够被Polycomb复合物亚基EZH2招募到HOXB13基因启动子处进而抑制HOXB13基因的表达。总之,我们的研究工作阐述了HOXB13基因沉默机制以及其对前列腺癌细胞生长的影响,这些发现也暗示了HOXB13可能作为前列腺癌治疗的一个分子靶标。
HOXB13 is a homeodomain protein implicated to play a role in growth arrest in prostate cancer cells. Expression of HOXB13 is restricted to the AR (androgen receptor)-expressing prostate cells; however, the mechanism underlying this silencing has not been fully understood. In this study, we investigated the possible regulatory mechanisms and roles of epigenetic modifications in HOXB13 gene transcription. We demonstrate that the HDAC inhibitor sodium butyrate (NaB) was able to induce cell growth arrest and to increase HOXB13 expression in AR-negative prostate cancer cells. Results arising our study revealed that both histone deacetylase HDAC4 and transcript factor YY1 could regulate HOXB13 gene at the levels of promoter activity, mRNA and protein expression. Moreover, we show that both HDAC4 and YY1 participated in the repression of HOXB13 expression through an epigenetic mechanism involving histone acetylation modification. Specifically, co-immuno- precipitation (CoIP) assays revealed that HDAC4 and YY1 formed a complex. The chromatin immunoprecipitation (ChIP) assays verified that HDAC4 was recruited to HOXB13 promoter by YY1. Additionally, promoter truncation and point mutation studies determined that the two proximal YY1 binding sites on the HOXB13 promoter were essential for the recruitments of YY1 and HDAC4. Results from MTT assays suggested that YY1 and HDAC4 affected cell growth through repressing the transcription of HOXB13 gene. Meanwhile, we found that the siRNA-induced partial silencing of Polycomb group proteins EZH2 and BMI1 resulted in a significant upregulation of both HOXB13 mRNA and protein levels in AR-negative prostate cancer cells. The ChIP assays demonstrated that H3K27me3 played an important role in this process. Also, we showed that the methyltransferase inhibitor 5-aza-dC induced the recovery of HOXB13 mRNA and protein expression, and we further manifested that almost all the CpG sites at HOXB13 promoter were densely methylated in AR-negative prostate cancer cells. Our evidence also showed that DNMT3b was recruited to the HOXB13 promoter by EZH2 to inhibit HOXB13 expression. Altogether, data included in this thesis will contribute to elucidating the unique silencing mechanisms of HOXB13 transcription, as well as its effects on prostate cancer cell growth. These findings may also implicate the possibility of HOXB13 as a potential molecular therapeutic target for prostate cancer.
HOXB13 is a homeodomain protein implicated to play a role in growth arrest in prostate cancer cells. Expression of HOXB13 is restricted to the AR (androgen receptor)-expressing prostate cells; however, the mechanism underlying this silencing has not been fully understood. In this study, we investigated the possible regulatory mechanisms and roles of epigenetic modifications in HOXB13 gene transcription. We demonstrate that the HDAC inhibitor sodium butyrate (NaB) was able to induce cell growth arrest and to increase HOXB13 expression in AR-negative prostate cancer cells. Results arising our study revealed that both histone deacetylase HDAC4 and transcript factor YY1 could regulate HOXB13 gene at the levels of promoter activity, mRNA and protein expression. Moreover, we show that both HDAC4 and YY1 participated in the repression of HOXB13 expression through an epigenetic mechanism involving histone acetylation modification. Specifically, co-immuno- precipitation (CoIP) assays revealed that HDAC4 and YY1 formed a complex. The chromatin immunoprecipitation (ChIP) assays verified that HDAC4 was recruited to HOXB13 promoter by YY1. Additionally, promoter truncation and point mutation studies determined that the two proximal YY1 binding sites on the HOXB13 promoter were essential for the recruitments of YY1 and HDAC4. Results from MTT assays suggested that YY1 and HDAC4 affected cell growth through repressing the transcription of HOXB13 gene. Meanwhile, we found that the siRNA-induced partial silencing of Polycomb group proteins EZH2 and BMI1 resulted in a significant upregulation of both HOXB13 mRNA and protein levels in AR-negative prostate cancer cells. The ChIP assays demonstrated that H3K27me3 played an important role in this process. Also, we showed that the methyltransferase inhibitor 5-aza-dC induced the recovery of HOXB13 mRNA and protein expression, and we further manifested that almost all the CpG sites at HOXB13 promoter were densely methylated in AR-negative prostate cancer cells. Our evidence also showed that DNMT3b was recruited to the HOXB13 promoter by EZH2 to inhibit HOXB13 expression. Altogether, data included in this thesis will contribute to elucidating the unique silencing mechanisms of HOXB13 transcription, as well as its effects on prostate cancer cell growth. These findings may also implicate the possibility of HOXB13 as a potential molecular therapeutic target for prostate cancer.
引文
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