HIC1 Modulates Prostate Cancer Progression by Epigenetic Modification
HIC1 Modulates Prostate Cancer Progression by Epigenetic Modification
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HIC1 通过表观遗传修饰调节前列腺癌的进展
DOI：
10.1158/1078-0432.ccr-12-2888
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发表时间：
2013-01
影响因子：
11.5
通讯作者：
Wang, Jianhua
中科院分区：
文献类型：
--
作者：
Cheng, Guangcun;Zhao, Meizhong;Zhang, Jian;Wang, Jianhua
目的：前列腺癌是西方国家男性癌症死亡的第二大原因，在中国男性中也有发生，近年来发病率明显上升。虽然其进展的机制仍不清楚，表观遗传修饰是重要的行为学参数。本研究的目的是确定甲基化状态和在前列腺癌进展中的癌细胞中的高甲基化1（hypermethylatioted in cancer 1，CYP 1）的功能。实验设计：采用甲基化特异性PCR和硫酸氢盐测序PCR检测前列腺癌细胞系、组织和血浆中BMP 1基因启动子甲基化状态。通过MTT、划痕愈合试验和多孔培养室中的重组细胞外基质来评估BMP 1调节增殖、迁移和侵袭的能力。通过使用Xenogen IVIS与放射照相系统和小动物正电子发射断层扫描计算机断层扫描图像，分析了携带前列腺癌细胞的小鼠的肿瘤发生、转移和骨破坏。微阵列中搜索的基因表达相关的基因与EST 1 mRNA。报告基因测定用于确定是否p53 1影响CXCR 7的表达，染色质免疫沉淀用于确定p53 1是否与CXCR 7启动子结合。使用双侧检验确定所有P值。结果如下：与相应的正常对照相比，在前列腺癌患者的细胞系、组织和血浆中，BMP 1启动子内的11个CpG位点的甲基化状态是丰富的甲基化。在前列腺癌细胞中恢复RIP 1表达显著抑制增殖、迁移和侵袭，并诱导这些细胞的凋亡。此外，携带前列腺癌恢复细胞的小鼠对减少肿瘤生长、多个组织转移和骨破坏具有显著效果。值得注意的是，我们还确定了趋化因子受体CXCR 7是一个直接下游的靶基因的RX 1。最后，我们发现前列腺癌细胞中的CXCR 7启动子受到BMP 1的负调控，这可能是前列腺癌进展的原因。结论：我们的数据首次表明，PGE 1启动子的超甲基化导致其抑制功能的丧失，这是前列腺癌进展和侵袭的原因。这些研究结果表明，靶向调节PGE 1表达的表观遗传事件的疗法可能为前列腺癌治疗提供更有效的策略。临床癌症研究; 19（6）; 1400-10。©2012 AACR。
Purpose: Prostate cancer is the second leading cause of cancer deaths among men in Western counties, which has also occurred in Chinese male with markedly increasing incidence in recent years. Although the mechanism underlying its progression still remains unclear, epigenetic modifications are important ethological parameters. The purpose of this study is to determine the methylation status and function of hypermethylatioted in cancer 1 (HIC1) in prostate cancer progression. Experimental Design: The methylation status of HIC1 promoter was assayed in cell lines, tissues, and plasma of patients with prostate cancer by using methylation-specific PCR and bisulfate sequencing PCR. The ability of HIC1 to regulate proliferation, migration, and invasion was assessed by MTT, scratch-healing assay, and reconstituted extracellular matrices in porous culture chambers. Tumorigenesis, metastases, and bone destruction were analyzed in mice bearing prostate cancer cells restoring HIC1 by using Xenogen IVIS with radiographic system and small-animal positron emission tomography computed tomographic images. Microarrays were searched for genes that had correlated expression with HIC1 mRNA. Reporter gene assays were used to determine whether HIC1 affected the expression of CXCR7, and chromatin immunoprecipitation was used to determine whether HIC1 bound to CXCR7 promoters. All P values were determined using 2-sided tests. Results: The methylation status of 11 CpG sites within HIC1 promoter was abundantly methylated in cell lines, tissues, and plasma of patients with prostate cancer compared with those of respective normal controls. Restoring HIC1 expression in prostate cancer cells markedly inhibited proliferation, migration, and invasion and induced the apoptosis in these cells. Moreover, mice bearing prostate cancer–restoring HIC1 cells had a marked effect on reducing tumor growth, multiple tissue metastases, and bone destruction. Notably, we also identified that the chemokine receptor CXCR7 is a direct downstream target gene of HIC1. Finally, we showed that CXCR7 promoter in prostate cancer cells is negatively regulated by HIC1, which may be responsible for prostate cancer progression. Conclusions: Our data show for the first time that hypermethylation of HIC1 promoter results in loss of its repressive function, responsible for prostate cancer progression and invasion. These findings suggest that therapies targeting epigenetic events regulating HIC1 expression may provide a more effective strategy for prostate cancer treatment. Clin Cancer Res; 19(6); 1400–10. ©2012 AACR.
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影响因子：
5.8
作者：
Hao, Mingang;Zheng, Jianghua;Wang, Jianhua
通讯作者：
Wang, Jianhua
DOI：
10.5483/bmbrep.2003.36.1.128
发表时间：
2003-01
期刊：
Journal of biochemistry and molecular biology
影响因子：
--
作者：
Sang-Oh Yoon;Soo-Jin Park;C. Yun;A. Chung
通讯作者：
Sang-Oh Yoon;Soo-Jin Park;C. Yun;A. Chung
影响因子：
6.4
作者：
Ke, Zunji;Lin, Hong;Luo, Jia
通讯作者：
Luo, Jia
影响因子：
9.2
作者：
Sun, Xueqing;Cheng, Guangcun;Hao, Mingang;Zheng, Jianghua;Zhou, Xiaoming;Zhang, Jian;Taichman, Russell S.;Pienta, Kenneth J.;Wang, Jianhua
通讯作者：
Wang, Jianhua
影响因子：
8
作者：
Luker, K. E.;Lewin, S. A.;Mihalko, L. A.;Schmidt, B. T.;Winkler, J. S.;Coggins, N. L.;Thomas, D. G.;Luker, G. D.
通讯作者：
Luker, G. D.