Genome-wide transcriptional response to 5-aza-2′-deoxycytidine and trichostatin a in multiple myeloma cells
Genome-wide transcriptional response to 5-aza-2′-deoxycytidine and trichostatin a in multiple myeloma cells
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DOI：
10.1158/0008-5472.can-07-2531
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发表时间：
2008-01-01
期刊：
影响因子：
11.2
通讯作者：
Zoechbauer-Mueller, Sabine
中科院分区：
文献类型：
--
作者：
Heller, Gerwin;Schmidt, Wolfgang M.;Zoechbauer-Mueller, Sabine
为了鉴定表观遗传沉默的癌症相关基因，并确定5-aza-2'-脱氧胞苷（Aza-dC）和/或trichostatin A （TSA）在多发性骨髓瘤（MM）中的分子作用，我们通过微阵列分析分析了3种MM细胞系基因表达谱的全局变化。我们发现了几个基因的上调，这些基因的表观遗传沉默在MM中是众所周知的。然而，更重要的是，我们发现了大量表观遗传失活的癌症相关基因，这些基因参与各种生理过程，其在MM中的表观遗传调控迄今尚不清楚。此外，MM细胞系的药物治疗导致几种MM增殖相关因子（即MAF， CCND1/2， MYC, FGFR3， MMSET）的下调。选择10个Aza-dC和/或TSA上调基因（CPEB1、CD9、GJA1、BCL7c、GADD45G、AKAP12、TFPI2、CCNA1、SPARC和BNIP3），对6个MM细胞系、24个未确定意义单克隆γ病（MGUS）患者样本和111个MM患者样本进行甲基化分析。MGUS样本中这些基因的甲基化频率在0%至17%之间，MM样本中甲基化频率在5%至50%之间。有趣的是，SPARC和BNIP3的甲基化与MM患者较差的总生存率有统计学意义（P = 0.003和P = 0.017）。此外，通过免疫染色，在一部分MM患者中，SPARC甲基化与SPARC蛋白表达缺失相关。总之，我们发现了单克隆伽玛病中异常甲基化的新靶点，我们的结果表明DNA甲基转移酶和组蛋白去乙酰化酶抑制可能在未来治疗MM患者中发挥重要作用。
To identify epigenetically silenced cancer-related genes and to determine molecular effects of 5-aza-2'-deoxycytidine (Aza-dC) and/or trichostatin A (TSA) in multiple myeloma (MM), we analyzed global changes in gene expression profiles of three MM cell lines by microarray analysis. We identified up-regulation of several genes whose epigenetic silencing in MM is well known. However, much more importantly, we identified a large number of epigenetically inactivated cancer-related genes that are involved in various physiologic processes and whose epigenetic regulation in MM was unknown thus far. In addition, drug treatment of MM cell lines resulted in down-regulation of several MM proliferation-associated factors (i.e., MAF, CCND1/2, MYC, FGFR3, MMSET). Ten Aza-dC and/or TSA up-regulated genes (CPEB1, CD9, GJA1, BCL7c, GADD45G, AKAP12, TFPI2, CCNA1, SPARC, and BNIP3) were selected for methylation analysis in six MM cell lines, 24 samples from patients with monoclonal gammopathy of undetermined significance (MGUS), and 111 samples from patients with MM. Methylation frequencies of these genes ranged between 0% and 17% in MGUS samples and between 5% and 50% in MM samples. Interestingly, methylation of SPARC and BNIP3 was statistically significantly associated with a poor overall survival of MM patients (P = 0.003 and P = 0.017, respectively). Moreover, SPARC methylation was associated with loss of SPARC protein expression by immunostaining in a subset of MM patients. In conclusion, we identified new targets for aberrant methylation in monoclonal gammopathies, and our results suggest that DNA methyltransferase and histone deacetylase inhibition might play an important role in the future treatment of patients with MM.