Transcriptional suppression, DNA methylation, and histone deacetylation of the regulator of G-protein signaling 10 (RGS10) gene in ovarian cancer cells.
Transcriptional suppression, DNA methylation, and histone deacetylation of the regulator of G-protein signaling 10 (RGS10) gene in ovarian cancer cells.
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DOI：
10.1371/journal.pone.0060185
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hooks SB
中科院分区：
文献类型：
--
作者：
Ali MW;Cacan E;Liu Y;Pierce JY;Creasman WT;Murph MM;Govindarajan R;Eblen ST;Greer SF;Hooks SB
RGS10调控卵巢癌细胞的生长和存活，在卵巢癌化疗耐药的细胞模型中，RGS10的表达受到抑制。然而，调控RGS10在卵巢癌中表达的机制尚不清楚。在这里，我们报告了RGS10在原发卵巢癌和CAOV-3卵巢癌细胞中的抑制作用与永生化的卵巢表面上皮细胞(IOSE)的比较，以及在A2780-AD化疗耐药细胞中与亲代A2780细胞的比较。RGS10-1和RGS10-2转录本在卵巢癌细胞中有表达，而在A2780-AD和CAOV-3细胞中只有RGS10-1被抑制，并且RGS10-1启动子唯一的富含在CpG二核苷酸中。药物抑制DNA甲基转移酶(DNMT)可增加RGS10的表达，提示可能通过DNA甲基化进行调节。亚硫酸氢盐测序分析发现，与亲本A2780细胞相比，耐药A2780-AD细胞中RGS10-1启动子的一个区域的DNA甲基化显著增强。CAOV-3和IOSE细胞的DNA甲基化与A2780细胞相似。RGS10-1启动子的组蛋白乙酰化差异更显著。与RGS10-1启动子相关的乙酰化组蛋白H3在A2780-AD细胞中显著低于亲本细胞，而组蛋白脱乙酰酶(HDAC)酶关联相应增加。同样，在CAOV-3细胞中，RGS10-1启动子的乙酰化组蛋白水平明显低于IOSE细胞，并且在CAOV-3细胞中，HDAC1结合增加了一倍。最后，我们发现，在耐药的A2780-AD细胞中，DNMT或HDAC酶的药物抑制增加了RGS10的表达，并增强了顺铂的毒性。这些数据表明，组蛋白去乙酰化和DNA甲基化与卵巢癌中RGS10抑制和化疗耐药相关。RGS10表达缺失的标记物可以识别对治疗有独特反应的癌细胞。
RGS10 regulates ovarian cancer cell growth and survival, and RGS10 expression is suppressed in cell models of ovarian cancer chemoresistance. However, the mechanisms governing RGS10 expression in ovarian cancer are poorly understood. Here we report RGS10 suppression in primary ovarian cancer and CAOV-3 ovarian cancer cells compared to immortalized ovarian surface epithelial (IOSE) cells, and in A2780-AD chemoresistant cells compared to parental A2780 cells. RGS10-1 and RGS10-2 transcripts are expressed in ovarian cancer cells, but only RGS10-1 is suppressed in A2780-AD and CAOV-3 cells, and the RGS10-1 promoter is uniquely enriched in CpG dinucleotides. Pharmacological inhibition of DNA methyl-transferases (DNMTs) increased RGS10 expression, suggesting potential regulation by DNA methylation. Bisulfite sequencing analysis identified a region of the RGS10-1 promoter with significantly enhanced DNA methylation in chemoresistant A2780-AD cells relative to parental A2780 cells. DNA methylation in CAOV-3 and IOSE cells was similar to A2780 cells. More marked differences were observed in histone acetylation of the RGS10-1 promoter. Acetylated histone H3 associated with the RGS10-1 promoter was significantly lower in A2780-AD cells compared to parental cells, with a corresponding increase in histone deacetylase (HDAC) enzyme association. Similarly, acetylated histone levels at the RGS10-1 promoter were markedly lower in CAOV-3 cells compared to IOSE cells, and HDAC1 binding was doubled in CAOV-3 cells. Finally, we show that pharmacological inhibition of DNMT or HDAC enzymes in chemoresistant A2780-AD cells increases RGS10 expression and enhances cisplatin toxicity. These data suggest that histone de-acetylation and DNA methylation correlate with RGS10 suppression and chemoresistance in ovarian cancer. Markers for loss of RGS10 expression may identify cancer cells with unique response to therapeutics.
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