Suberoylanilide hydroxamic acid enhances gap junctional intercellular communication via acetylation of histone containing Connexin 43 gene locus.
Suberoylanilide hydroxamic acid enhances gap junctional intercellular communication via acetylation of histone containing Connexin 43 gene locus.
复制标题
DOI：
10.1158/0008-5472.can-05-0227
复制
发表时间：
2005-11-01
期刊：
影响因子：
11.2
通讯作者：
Yorioka, N
中科院分区：
文献类型：
--
作者：
Ogawa, T;Hayashi, T;Yorioka, N
辛二酰苯胺异羟肟酸（SABLA）是一种历史悠久的脱乙酰酶（HDAC）抑制剂，可诱导肿瘤细胞凋亡，但其对与凋亡相关的间隙连接细胞间通讯的影响尚不清楚。因此，我们对两种 HDAC 抑制剂 SAHA 和曲古抑菌素 A 对非恶性人腹膜间皮细胞 (HPMC) 和致瘤 ras 癌基因转化的大鼠肝上皮细胞 (WB-ras) 间隙连接细胞间通讯的影响进行了比较研究，结果显示间隙连接细胞间通讯水平显着低于 HDAC 抑制剂 SAHA 和曲古抑菌素 A。 做了HPMC。通过光漂白后荧光恢复的恢复率来评估间隙连接细胞间通讯。用纳摩尔浓度的 SARA 处理 HPMC 导致恢复率呈剂量依赖性增加，但不诱导细胞凋亡。这种效应伴随着连接蛋白 43 (Cx43) mRNA 和蛋白表达的增强以及细胞膜上 Cx43 蛋白的存在增加。 Trichostatin-A 诱导 HPMC 细胞凋亡，但在提高恢复率方面不如 SARA 有效。相比之下，用 SAHA 或曲古抑菌素 A 处理 WB-ras 细胞在低浓度下会诱导细胞凋亡，尽管恢复率、Cx43 mRNA 和蛋白质的增加幅度小于 HPMC。染色质免疫沉淀分析显示，SARA 增强了 HPMC 中与 Cs43 基因相关的染色质片段中的乙酰化历史 H3 和 H4。这些结果表明，由于选择性染色质片段中的组蛋白乙酰化，低浓度的 SAHA 选择性上调正常人细胞中的 Cx43 表达，而不诱导细胞凋亡，这与在致瘤 WB-ras 细胞中观察到的细胞凋亡效应相反。这些结果支持特定 HDAC 抑制剂的癌症治疗和预防作用。
A historic deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SABLA), induces apoptosis in neoplastic cells, but its effect on gap junctional intercellular communication in relation to apoptosis was unclear. Therefore, we carried out a comparative study of the effects of two HDAC inhibitors, SAHA and trichostatin-A, on gap junctional intercellular communication in nonmalignant human peritoneal mesothelial cells (HPMC) and tumorigenic ras oncogene-transformed rat liver epithelial cells (WB-ras) that showed a significantly lower level of gap junctional intercellular communication than did HPMC. Gap junctional intercellular communication was assessed by recovery rate of fluorescence recovery after photobleaching. Treatment of HPMC with SARA at nanomolar concentrations caused a dose-dependent increase of recovery rate without inducing apoptosis. This effect was accompanied by enhanced connexin 43 (Cx43) mRNA and protein expression and increased presence of Cx43 protein on cell membrane. Trichostatin-A induced apoptosis in HPMC but was less potent than SARA in enhancing the recovery rate. In contrast, treatment of WB-ras cells with SAHA or trichostatin-A induced apoptosis at low concentrations, in spite of smaller increases in recovery rate, Cx43 mRNA, and protein than in HPMC. Chromatin immunoprecipitation analysis revealed that SARA enhanced acetylated histories H3 and H4 in the chromatin fragments associated with Cs43 gene in HPMC. These results indicate that SAHA at low concentrations selectively up-regulates Cx43 expression in normal human cells without induction of apoptosis, as a result of histone acetylation in selective chromatin fragments, in contrast to the apoptotic effect observed in tumorigenic WB-ras cells. These results support a cancer therapeutic and preventive role for specific HDAC inhibitors.