Protein acetylation and histone deacetylase expression associated with malignant breast cancer progression.
Protein acetylation and histone deacetylase expression associated with malignant breast cancer progression.
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DOI：
10.1158/1078-0432.ccr-08-2319
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发表时间：
2009-05-01
期刊：
影响因子：
--
通讯作者：
Hwang ES
中科院分区：
文献类型：
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作者：
Suzuki J;Chen YY;Scott GK;Devries S;Chin K;Benz CC;Waldman FM;Hwang ES
过量的组蛋白去乙酰化酶（HDAC）活性可以诱导组蛋白和非组蛋白底物的低乙酰化，改变与恶性转化潜在相关的基因表达模式和细胞行为。然而，HDAC表达和蛋白乙酰化在乳腺癌进展中的作用尚未得到研究。我们采用免疫组化（IHC）方法评估了58例具有同步正常上皮(N)、导管原位癌（DCIS）和浸润性导管癌（IDC）成分的乳腺标本中乙酰化组蛋白H4 （ac-H4）、ac-H4K12、ac-微管蛋白、HDAC1、HDAC2和HDAC6的表达水平。采用非参数检验检验各组间IHC评分差异的显著性。从N到DCIS，组蛋白乙酰化明显降低（p<0.0001）。大多数病例在DCIS和IDC中显示相似的乙酰化水平，尽管有些病例显示ac-H4和ac-H4K12从DCIS到IDC进一步降低。hdac 1、2和6的表达也显著降低，但幅度较小。从N到DCIS， er阴性肿瘤中H4乙酰化和HDAC1水平的降低幅度大于er阳性，高级别肿瘤中H4乙酰化和HDAC1水平的降低幅度大于非高级别肿瘤。总体而言，从N到DCIS再到IDC的进展与低乙酰化的整体模式相关。矛盾的是，这与HDAC表达水平的降低有关，这表明这种低乙酰化模式反映了HDAC和组蛋白乙酰转移酶（HAT）催化活性之间平衡的变化。这些发现还表明，在DCIS和IDC中这种低乙酰化的逆转可能是HDAC抑制剂活性的早期测量指标。
Excess histone deacetylase (HDAC) activity can induce hypoacetylation of histone and non-histone protein substrates, altering gene expression patterns and cell behavior potentially associated with malignant transformation. However, HDAC expression and protein acetylation have not been studied in the context of breast cancer progression. We performed immunohistochemistry (IHC) to assess expression levels of acetylated histone H4 (ac-H4), ac-H4K12, ac-tubulin, HDAC1, HDAC2 and HDAC6 in 58 breast specimens with synchronous normal epithelium (N), ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) components. Differences in IHC scoring between groups were tested for significance using non-parametric tests. From N to DCIS, there was marked reduction in histone acetylation (p<0.0001). Most cases showed similar levels of acetylation in DCIS and IDC, although some showed further reduction of ac-H4 and ac-H4K12 from DCIS to IDC. Expression of HDACs 1, 2, and 6 were also significantly reduced but by a smaller magnitude. Greater reductions of H4 acetylation and HDAC1 levels were observed from N to DCIS in ER-negative compared to ER-positive, and in high grade tumors compared to non-high grade tumors. Overall, there was a global pattern of hypoacetylation associated with progression from N to DCIS to IDC. Paradoxically, this was associated with reduction in HDAC expression levels, suggesting that this hypoacetylation pattern reflects a change in the balance between HDAC and histone acetyltransferase (HAT) catalytic activities. These findings also suggest that the reversal of this hypoacetylation in DCIS and IDC could be an early measure of HDAC inhibitor activity.