HDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responses.
HDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responses.
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HDAC抑制剂诱导肿瘤 - 细胞选择性促凋亡转录反应。
DOI：
10.1038/cddis.2013.9
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发表时间：
2013-02-28
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
鉴定编码表观遗传酶的基因中的复发性体细胞突变为开发靶向表观基因组用于治疗癌症的化合物提供了强有力的理论基础。这一观点得到了生物化学研究的支持，这些研究表明表观遗传酶（如组蛋白脱乙酰酶（HDAC）和组蛋白甲基转移酶）通过与致癌融合蛋白（如PML-RARα和AML 1-ETO）相关而异常募集至启动子区域。HDAC抑制剂（HDACi）是肿瘤细胞凋亡的有效诱导剂;然而，仍不清楚为什么肿瘤细胞比正常细胞对HDACi诱导的细胞死亡更敏感。在本文中，我们评估了同基因正常和转化细胞对FDA批准的HDACi伏立诺他和罗米地辛的生物学和分子反应。两种HDACi都选择性地杀死通过连续引入不同癌基因而转化的不同组织来源的细胞。时程微阵列表达谱显示正常和转化细胞对伏立诺他治疗有转录应答。超过4200个基因在正常和转化细胞中对伏立诺他有不同的反应，基因本体和途径分析鉴定了由BCL 2家族基因组成的肿瘤细胞选择性促凋亡基因表达特征。特别地，HDACi诱导促凋亡基因BMF的肿瘤细胞选择性上调和编码BFL-1的促存活基因BCL 2A 1的下调。通过强制表达维持转化细胞中的BFL-1水平赋予伏立诺他抗性，表明特异性和选择性参与内在凋亡途径是这些药物的肿瘤细胞选择性凋亡活性的基础。HDACi影响肿瘤细胞的生长和存活同时使正常细胞相对不受伤害的能力是其成功临床应用的基础。这项研究为HDACi在人类供体匹配的正常和转化细胞中的转录作用提供了新的见解，并暗示了这些化合物的肿瘤选择性细胞毒性活性中的特定分子和途径。
The identification of recurrent somatic mutations in genes encoding epigenetic enzymes has provided a strong rationale for the development of compounds that target the epigenome for the treatment of cancer. This notion is supported by biochemical studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases to promoter regions through association with oncogenic fusion proteins such as PML-RARα and AML1-ETO. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis; however, it remains unclear why tumor cells are more sensitive to HDACi-induced cell death than normal cells. Herein, we assessed the biological and molecular responses of isogenic normal and transformed cells to the FDA-approved HDACi vorinostat and romidepsin. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time-course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontology and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor-cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance, indicating that specific and selective engagement of the intrinsic apoptotic pathway underlies the tumor-cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells whilst leaving normal cells relatively unharmed is fundamental to their successful clinical application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and implicates specific molecules and pathways in the tumor-selective cytotoxic activity of these compounds.
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DOI：
10.1111/j.1349-7006.2001.tb02153.x
发表时间：
2001-12
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Choi JH;Kwon HJ;Yoon BI;Kim JH;Han SU;Joo HJ;Kim DY
通讯作者：
Kim DY
影响因子：
3.3
作者：
Grant C;Rahman F;Piekarz R;Peer C;Frye R;Robey RW;Gardner ER;Figg WD;Bates SE
通讯作者：
Bates SE
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
12.4
作者：
Labi V;Grespi F;Baumgartner F;Villunger A
通讯作者：
Villunger A
影响因子：
11.4
作者：
Inoue, S.;Riley, J.;Cohen, G. M.
通讯作者：
Cohen, G. M.