HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer
HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer
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DOI：
10.1038/onc.2016.344
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发表时间：
2017-03-30
期刊：
影响因子：
8
通讯作者：
Schneider, G.
中科院分区：
文献类型：
--
作者：
Stojanovic, N.;Hassan, Z.;Schneider, G.
p53突变是胰腺癌中常见的遗传性病变，是一个尚未解决的临床挑战。p53的突变体已经失去了野生型p53的肿瘤抑制功能。此外，p53突变体发挥肿瘤促进功能，使其成为重要的治疗靶点。在这里，我们表明，I类组蛋白去乙酰化酶HDAC 1和HDAC 2有助于维持p53突变体在人类和遗传定义的小鼠胰腺癌细胞中的表达。我们的数据显示，用小分子HDAC抑制剂（HDACi）抑制这些HDAC，以及HDAC 1和HDAC 2的特异性遗传消除，降低了突变型p53 mRNA和蛋白水平的表达。我们进一步表明，HDAC 1，HDAC 2和MYC直接结合到TP 53基因和MYC招聘后HDAC抑制剂治疗下降。因此，我们的研究结果说明了以前未被识别的I类HDAC依赖性TP 53基因的控制，并提供了MYC贡献的证据。靶向HDAC 1/HDAC 2和MYC的组合方法可能为靶向胰腺癌中的突变型p53提供一种新的分子定义的策略。
Mutation of p53 is a frequent genetic lesion in pancreatic cancer being an unmet clinical challenge. Mutants of p53 have lost the tumour-suppressive functions of wild type p53. In addition, p53 mutants exert tumour-promoting functions, qualifying them as important therapeutic targets. Here, we show that the class I histone deacetylases HDAC1 and HDAC2 contribute to maintain the expression of p53 mutants in human and genetically defined murine pancreatic cancer cells. Our data reveal that the inhibition of these HDACs with small molecule HDAC inhibitors (HDACi), as well as the specific genetic elimination of HDAC1 and HDAC2, reduce the expression of mutant p53 mRNA and protein levels. We further show that HDAC1, HDAC2 and MYC directly bind to the TP53 gene and that MYC recruitment drops upon HDAC inhibitor treatment. Therefore, our results illustrate a previously unrecognized class I HDAC-dependent control of the TP53 gene and provide evidence for a contribution of MYC. A combined approach targeting HDAC1/HDAC2 and MYC may present a novel and molecularly defined strategy to target mutant p53 in pancreatic cancer.