The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells.
The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells.
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发表时间：
2001-12
期刊：
影响因子：
11.2
通讯作者：
P. Munster;T. Troso-Sandoval;N. Rosen;R. Rifkind;PA Marks;V. Richon
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作者：
P. Munster;T. Troso-Sandoval;N. Rosen;R. Rifkind;PA Marks;V. Richon
组蛋白去乙酰化酶（HDAC）通过催化核心核小体组蛋白NH（2）-端赖氨酸残基上的乙酰基的去除来调节组蛋白乙酰化。核心组蛋白乙酰化状态的调节涉及某些基因转录活性的调节。HDAC活性通常与转录抑制相关。HDAC活性的异常募集与某些人类癌症的发展有关。我们已经开发了一类HDAC抑制剂，如辛二酰苯胺异羟肟酸（SAHA），最初是根据它们诱导培养的小鼠红白血病细胞分化的能力来鉴定的。其他研究表明，SAHA抑制啮齿动物肿瘤的生长。在这项研究中，我们研究了SAHA对MCF-7人乳腺癌细胞的影响。我们发现SAHA以剂量依赖的方式抑制细胞增殖，在细胞周期的G（1）-G（2）-M期积累细胞，并诱导乳脂球蛋白、乳脂膜球蛋白和脂滴。生长抑制与形态学变化相关，包括细胞质的扁平化和扩大，以及核质比的降低。撤去SAHA导致细胞重新进入细胞周期并逆转为分化程度较低的表型。SAHA在雌激素受体阴性细胞系SKBr-3和视网膜母细胞瘤阴性细胞系MDA-468中诱导分化。我们认为，SAHA通过使这些细胞经历依赖于SAHA存在的细胞周期停滞和分化而具有深刻的抗增殖活性。SAHA和其他HDAC抑制剂目前正在进行I期临床试验。这些发现可能会影响这些药物的临床使用。
Histone deacetylase (HDACs) regulate histone acetylation by catalyzing the removal of acetyl groups on the NH(2)-terminal lysine residues of the core nucleosomal histones. Modulation of the acetylation status of core histones is involved in the regulation of the transcriptional activity of certain genes. HDAC activity is generally associated with transcriptional repression. Aberrant recruitment of HDAC activity has been associated with the development of certain human cancers. We have developed a class of HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), that were initially identified based on their ability to induce differentiation of cultured murine erythroleukemia cells. Additional studies have demonstrated that SAHA inhibits the growth of tumors in rodents. In this study we have examined the effects of SAHA on MCF-7 human breast cancer cells. We found that SAHA causes the inhibition of proliferation, accumulation of cells in a dose-dependent manner in G(1) then G(2)-M phase of the cell cycle, and induction of milk fat globule protein, milk fat membrane globule protein, and lipid droplets. Growth inhibition was associated with morphological changes including the flattening and enlargement of the cytoplasm, and a decrease in the nuclear:cytoplasmic ratio. Withdrawal of SAHA led to reentry of cells into the cell cycle and reversal to a less differentiated phenotype. SAHA induced differentiation in the estrogen receptor-negative cell line SKBr-3 and the retinoblastoma-negative cell line MDA-468. We propose that SAHA has profound antiproliferative activity by causing these cells to undergo cell cycle arrest and differentiation that is dependent on the presence of SAHA. SAHA and other HDAC inhibitors are currently in Phase I clinical trials. These findings may impact the clinical use of these drugs.