Induction of TAp63 by histone deacetylase inhibitors
Induction of TAp63 by histone deacetylase inhibitors
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DOI：
10.1016/j.bbrc.2009.12.147
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发表时间：
2010-01-22
影响因子：
3.1
通讯作者：
Melino, Gerry
中科院分区：
文献类型：
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作者：
Sayan, Berna S.;Yang, Ai Li;Melino, Gerry
TAp 63属于p53-肿瘤抑制因子家族，能够反式激活一组靶基因以诱导细胞周期停滞和凋亡。我们发现用化疗药物或组蛋白脱乙酰酶（HDAC）抑制剂曲古抑菌素A（TSA）处理癌细胞导致诱导TAp 63表达，这反过来与化疗敏感性相关。事实上，TSA对TAp 63的诱导通过活性半胱天冬酶切割TAp 63的反式抑制结构域来影响对化疗药物的敏感性，从而导致产生转录超活性的TAp 63片段。因此，增强TAp 63表达的治疗方法可能会改善化疗耐药肿瘤的管理。在这项研究中，我们测试了不同HDAC抑制剂诱导TAp 63表达的能力。我们发现，属于异羟肟酸组的两种HDAC抑制剂，即TSA和LBH 589，是TAp 63表达的最有效的诱导剂。最后，我们发现HCT 116细胞中TAp 63表达的诱导依赖于p53，因为p53阴性HCT 116细胞在用不同HDAC抑制剂处理后未能诱导显著的TAp 63表达。(C)2009 Elsevier Inc. All rights reserved.
TAp63 belongs to the p53-tumour suppressor family and is capable of transactivating a set of target genes to induce cell cycle arrest and apoptosis. We showed that treatment of cancer cells with chemo-therapeutic drugs or the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) results in induction of TAp63 expression, which is in turn related with chemosensitivity. Indeed, induction of TAp63 by TSA affects sensitivity to chemo-therapeutic drugs via the cleavage of the trans-inhibitory domain of TAp63 by active caspases, resulting in generation of a transcriptionally hyper-active TAp63 fragment. Therefore therapeutic approaches that enhance TAp63 expression may offer an improvement in the management of chemoresistant tumours. In this study we tested the abilities of different HDAC inhibitors to induce TAp63 expression. We discovered that two HDAC inhibitors belonging to the hydroxamate group, namely TSA and LBH589, are the most efficient inducers of TAp63 expression. Finally, we found that induction of TAp63 expression in HCT1 16 cells depends on p53, as p53-negative HCT1 16 cells failed to induce significant TAp63 expression following treatment with different HDAC inhibitors. (C) 2009 Elsevier Inc. All rights reserved.