TP53-independent function of miR-34a via HDAC1 and p21(CIP1/WAF1.).
TP53-independent function of miR-34a via HDAC1 and p21(CIP1/WAF1.).
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DOI：
10.1038/mt.2013.148
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
Jane Zhao;P. Lammers;C. Torrance;A. Bader
中科院分区：
文献类型：
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作者：
Jane Zhao;P. Lammers;C. Torrance;A. Bader
肿瘤抑制因子microRNA-34(miR-34)是TP53的转录靶点，它在正反馈环中作用于激活TP53。虽然miR-34可以抑制携带TP53突变的癌细胞，但这种对TP53的反馈可能是miR-34发挥全部功能的先决条件，并可能限制其治疗应用于完整的TP53患者。为了研究TP53和miR-34之间的功能关系，以及包括miR-215/192在内的其他TP53调控的miRNAs的功能关系，我们使用了一组仅在内源性TP53状态方面存在差异的等基因癌细胞株。在TP53阳性和TP53阴性的细胞中，MIR-34对癌细胞生长的抑制作用是相同的。相比之下，miR-215/192通过TP53发挥作用。在没有TP53的情况下，miR-34，但不是miR-215/192，足以诱导细胞周期依赖的激酶抑制物p21CIP1/WAF1上调。我们发现组蛋白脱乙酰酶1(HDAC1)是miR-34的直接靶点，并证明了HDAC1的抑制导致p21CIP1/WAF1的诱导，并模仿miR-34的细胞表型。P21CIP1/WAF1的缺失特异性干扰miR-34抑制癌细胞增殖的能力。这些数据表明，miR-34控制着先前为TP53保留的肿瘤抑制通路，并为癌症患者提供了一种有吸引力的治疗策略，而无论TP53状态如何。
The tumor suppressor, microRNA-34 (miR-34), a transcriptional target of TP53, functions in a positive feedback loop to activate TP53. Although miR-34 can inhibit cancer cells carrying TP53 mutations, this feedback to TP53 may be a prerequisite for full miR-34 function and may restrict its therapeutic application to patients with intact TP53. To investigate the functional relationships between TP53 and miR-34, and that of other TP53-regulated miRNAs including miR-215/192, we have used a panel of isogenic cancer cell lines that differ only with respect to their endogenous TP53 status. miR-34–induced inhibition of cancer cell growth is the same in TP53-positive and TP53-negative cells. In contrast, miR-215/192 functions through TP53. In the absence of TP53, miR-34, but not miR-215/192, is sufficient to induce an upregulation of the cell cycle-dependent kinase inhibitor p21CIP1/WAF1. We identify histone deacetylase 1 (HDAC1) as a direct target of miR-34 and demonstrate that repression of HDAC1 leads to an induction of p21CIP1/WAF1and mimics the miR-34 cellular phenotype. Depletion of p21CIP1/WAF1specifically interferes with the ability of miR-34 to inhibit cancer cell proliferation. The data suggest that miR-34 controls a tumor suppressor pathway previously reserved for TP53 and provides an attractive therapeutic strategy for cancer patients irrespective of TP53 status.