Runt-related transcription factor 2 (RUNX2) inhibits p53-dependent apoptosis through the collaboration with HDAC6 in response to DNA damage.
Runt-related transcription factor 2 (RUNX2) inhibits p53-dependent apoptosis through the collaboration with HDAC6 in response to DNA damage.
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DOI：
10.1038/cddis.2013.127
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发表时间：
2013-04-25
影响因子：
9
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中科院分区：
文献类型：
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Runt-related transcription factor 2（RUNX 2）是成骨细胞分化的重要蛋白质。在这项研究中，我们首次发现RUNX 2作为p53的负调节因子响应DNA损伤。在阿霉素（ADR）暴露介导的DNA损伤中，p53和RUNX 2在人骨肉瘤衍生的U2 OS细胞中在蛋白和mRNA水平上被诱导，并与各种p53靶基因的显着上调相关。间接免疫染色和免疫共沉淀实验表明，ADR处理后，RUNX 2与p53共定位于细胞核中，并与p53形成复合物。染色质免疫沉淀分析显示，RUNX 2/p53复合物被有效地招募到p53靶启动子上，这表明RUNX 2可能参与调节p53介导的转录激活。事实上，RUNX 2的强制表达导致p53靶基因的显著下调。与这些观察结果一致，RUNX 2的敲低增强了ADR介导的细胞凋亡，并且也升高了p53靶基因对ADR的反应表达。另一方面，在p53缺陷型人肺癌衍生的H1299细胞中，RUNX 2的耗竭对p53靶基因的表达具有不可检测的影响，无论ADR处理如何，这表明RUNX 2介导的p53靶基因的下调依赖于p53。此外，RUNX 2/p53复合物包括组蛋白脱乙酰基酶6（HDAC 6），并且在ADR暴露后HDAC 6也被募集到p53靶启动子上。值得注意的是，HDAC 6特异性化学抑制剂tubacin处理增强了ADR介导的p53靶基因表达上调，表明HDAC 6的脱乙酰酶活性是RUNX 2介导的p53靶基因下调所必需的。总之，我们目前的研究结果强烈表明，RUNX 2抑制DNA损伤诱导的转录以及p53的促凋亡活性，通过与HDAC 6的功能合作，因此可能是一个有吸引力的治疗癌症的治疗靶点。
Runt-related transcription factor 2 (RUNX2) is the best known as an essential protein for osteoblast differentiation. In this study, we have found for the first time that RUNX2 acts as a negative regulator for p53 in response to DNA damage. On DNA damage mediated by adriamycin (ADR) exposure, p53 as well as RUNX2 was induced at protein and mRNA level in human osteosarcoma-derived U2OS cells in association with a significant upregulation of various p53-target genes. Indirect immunostaining and co-immunoprecipitation experiments demonstrated that RUNX2 colocalizes with p53 in cell nucleus and forms a complex with p53 following ADR treatment. Chromatin immunoprecipitation assays revealed that RUNX2/p53 complex is efficiently recruited onto p53-target promoters in response to ADR, suggesting that RUNX2 might be involved in the regulation of transcriptional activation mediated by p53. Indeed, forced expression of RUNX2 resulted in a remarkable downregulation of p53-target genes. Consistent with these observations, knockdown of RUNX2 enhanced ADR-mediated apoptosis and also elevated p53-target gene expression in response to ADR. On the other hand, depletion of RUNX2 in p53-deficient human lung carcinoma-derived H1299 cells had an undetectable effect on p53-target gene expression regardless of ADR treatment, indicating that RUNX2-mediated downregulation of p53-target genes is dependent on p53. Furthermore, RUNX2/p53 complex included histone deacetylase 6 (HDAC6) and HDAC6 was also recruited onto p53-target promoters following ADR exposure. Of note, HDAC6-specific chemical inhibitor tubacin treatment enhanced ADR-mediated upregulation of p53-target gene expression, indicating that deacetylase activity of HDAC6 is required for RUNX2-mediated downregulation of p53-target gene. Taken together, our present findings strongly suggest that RUNX2 inhibits DNA damage-induced transcriptional as well as pro-apoptotic activity of p53 through the functional collaboration with HDAC6 and therefore might be an attractive therapeutic target for cancer treatment.
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