Histone deacetylase inhibitors suppress mutant p53 transcription via HDAC8/YY1 signals in triple negative breast cancer cells
Histone deacetylase inhibitors suppress mutant p53 transcription via HDAC8/YY1 signals in triple negative breast cancer cells
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组蛋白脱乙酰酶抑制剂通过三阴性乳腺癌细胞中的 HDAC8/YY1 信号抑制突变 p53 转录
DOI：
10.1016/j.cellsig.2016.02.006
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发表时间：
2016-05-01
影响因子：
4.8
通讯作者：
Wang, Hong-Sheng
中科院分区：
文献类型：
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作者：
Wang, Zhao-Tong;Chen, Zhuo-Jia;Wang, Hong-Sheng
迫切需要研究三阴性乳腺癌（TNBC）的潜在靶向治疗方法。本研究表明，组蛋白去乙酰化酶抑制剂（HDACIs）亚酰苯胺羟肟酸（SAHA）和丁酸钠（NaB）显著抑制TNBC细胞增殖，使细胞周期停留在G0/G1期，并诱导线粒体相关凋亡。此外，SAHA和NaB降低TNBC细胞中突变型p53 （mtp53）的磷酸化、蛋白和mRNA水平。而SAHA或NaB对野生型p53 （wtp53）没有类似的抑制作用。这种抑制明显发生在转录水平上，因为前体p53转录的下调比成熟p53的下调要快得多（不到2小时）和剧烈得多。在TNBC细胞中，HDAC8的敲低抑制了mtp53的转录，而HDAC6的敲低则没有。荧光素酶实验和ChIP分析显示SAHA和NaB均能降低转录因子阴阳1 （YY1）与人p53启动子-102 ~ -96位点的结合。YY1的敲低也显著抑制TNBC细胞mtp53的转录。此外，SAHA和NaB可抑制HDAC8与YY1的结合，使YY1残基170-200乙酰化程度升高，进而降低其转录活性，最终抑制YY1诱导的p53转录。总之，我们的数据表明SAHA和NaB可以被认为是TNBC患者的候选药物，HDAC8/YY1/mtp53信号是TNBC治疗的重要靶点。(C) 2016 Elsevier Inc.版权所有。
There is an urgent need to investigate the potential targeted therapy approach for triple-negative breast cancer (TNBC). Our present study reveals that histone deacetylase inhibitors (HDACIs) suberoyl anilide hydroxamic acid (SAHA) and sodium butyrate (NaB) significantly inhibit cell proliferation, arrest cell cycle at G0/G1 phase, and induce mitochondrial related apoptosis of TNBC cells. Further, SAHA and NaB decrease the phosphorylation, protein and mRNA levels of mutant p53 (mtp53) in TNBC cells. While SAHA or NaB has no similar inhibition effect on wild type p53 (wtp53). The inhibition apparently occurs at the level of transcription because the down regulation of precursor p53 transcription is much more rapid (less than 2 h) and sharp than that of mature p53. The knockdown of HDAC8, while not HDAC6, inhibits the transcription of mtp53 in TNBC cells. The luciferase assay and ChIP analysis reveal that both SAHA and NaB can reduce the binding of transcription factor Yin Yang 1 (YY1) with the -102 to -96 position of human p53 promoter. Knockdown of YY1 also significantly inhibits the transcription of mtp53 in TNBC cells. Further, SAHA and NaB can inhibit the association of HDAC8 and YY1, increase acetylation of residues 170-200 of YY1, then decrease its transcription activities, and finally suppress YY1 induced p53 transcription. Together, our data establish that SAHA and NaB can be considered as drug candidates for TNBC patients, and HDAC8/YY1/mtp53 signals act as an important target for TNBC treatment. (C) 2016 Elsevier Inc. All rights reserved.