Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer
Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer
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DOI：
10.1038/sj.onc.1208646
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发表时间：
2005-06-30
期刊：
影响因子：
8
通讯作者：
Toi, M
中科院分区：
文献类型：
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作者：
Saji, S;Kawakami, M;Toi, M
组蛋白脱乙酰酶（HDAC）6是HDAC家族的一个亚型;它使α-微管蛋白脱乙酰并增加细胞运动性。在这里，我们研究了雌激素受体a（ER）阳性乳腺癌MCF-7细胞中HDAC 6表达改变的影响，因为我们确定HDAC 6是一种新的雌激素调节基因。用雌二醇处理的MCF-7显示HDAC 6 mRNA和蛋白的表达增加，并且在迁移试验中细胞运动性增加4倍。通过将HDAC 6表达载体稳定转染到MCF-7细胞中，细胞运动性增加到相同程度。在这两种情况下，细胞的外观都从原来的圆形变成了轴突延伸的形状，就像神经元细胞一样。这种HDAC 6积累引起α-微管蛋白的脱乙酰化。选择性雌激素受体调节剂他莫昔芬（TAM）或纯抗雌激素ICI 182，780阻止雌二醇诱导的HDAC 6积累和α-微管蛋白的脱乙酰化，导致细胞运动性降低。Tubacin是一种与HDAC 6的微管蛋白脱乙酰化结构域结合的抑制性分子，也能阻止雌二醇刺激的细胞迁移。最后，我们通过免疫组化染色评估了HDAC 6蛋白在139例连续存档的人乳腺癌组织中的表达。这些患者的预后分析显示，基于HDAC 6表达没有显著差异。然而，对接受TAM辅助治疗的ER阳性患者（n = 67）的亚组分析显示，HDAC 6阳性组的无复发生存率和总生存率存在统计学显著差异（分别为P < 0.02和P < 0.05）。多因素分析显示HDAC 6表达是独立的预后指标（OR = 2.82，P = 0.047）。这些结果表明HDAC 6通过雌激素信号调节的生物学意义。
Histone deacetylase ( HDAC) 6 is a subtype of the HDAC family; it deacetylates alpha-tubulin and increases cell motility. Here, we investigate the impact of an alteration of HDAC6 expression in estrogen receptor a ( ER)positive breast cancer MCF-7 cells, as we identified that HDAC6 is a novel estrogen-regulated gene. MCF-7 treated with estradiol showed increased expression of HDAC6 mRNA and protein and a four-fold increase in cell motility in a migration assay. Cell motility was increased to the same degree by stably transfecting the HDAC6 expression vector into MCF-7 cells. In both cases, the cells changed in appearance from their original round shape to an axon-extended shape, like a neuronal cell. This HDAC6 accumulation caused the deacetylation of alpha-tubulin. Either the selective estrogen receptor modulator tamoxifen (TAM) or the pure antiestrogen ICI 182,780 prevented estradiol-induced HDAC6 accumulation and deacetylation of alpha-tubulin, leading to reduced cell motility. Tubacin, an inhibitory molecule that binds to the tubulin deacetylation domain of HDAC6, also prevented estradiol-stimulated cell migration. Finally, we evaluated HDAC6 protein expression in 139 consecutively archived human breast cancer tissues by immunohistochemical staining. The prognostic analyses for these patients revealed no significant differences based on HDAC6 expression. However, subset analysis of ER-positive patients who received adjuvant treatment with TAM (n = 67) showed a statistically significant difference in relapse-free survival and overall survival in favor of the HDAC6-positive group (P < 0.02 and P < 0.05, respectively). HDAC 6 expression was an independent prognostic indicator by multivariate analysis ( odds ratio = 2.82, P = 0.047). These results indicate the biological significance of HDAC6 regulation via estrogen signaling.