Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Nucleic Acids Res. 2013 Jul;41(12):6018-33. doi: 10.1093/nar/gkt346. Epub 2013 Apr 26.
MYCN is a master regulator controlling many processes necessary for tumor cell survival. Here, we unravel a microRNA network that causes tumor suppressive effects in MYCN-amplified neuroblastoma cells. In profiling studies, histone deacetylase (HDAC) inhibitor treatment most strongly induced miR-183. Enforced miR-183 expression triggered apoptosis, and inhibited anchorage-independent colony formation in vitro and xenograft growth in mice. Furthermore, the mechanism of miR-183 induction was found to contribute to the cell death phenotype induced by HDAC inhibitors. Experiments to identify the HDAC(s) involved in miR-183 transcriptional regulation showed that HDAC2 depletion induced miR-183. HDAC2 overexpression reduced miR-183 levels and counteracted the induction caused by HDAC2 depletion or HDAC inhibitor treatment. MYCN was found to recruit HDAC2 in the same complexes to the miR-183 promoter, and HDAC2 depletion enhanced promoter-associated histone H4 pan-acetylation, suggesting epigenetic changes preceded transcriptional activation. These data reveal miR-183 tumor suppressive properties in neuroblastoma that are jointly repressed by MYCN and HDAC2, and suggest a novel way to bypass MYCN function.
MYCN 是一个主控调节因子，控制着肿瘤细胞生存所需的许多过程。在这里，我们揭示了一个 microRNA 网络，它在 MYCN 扩增的神经母细胞瘤细胞中引起肿瘤抑制作用。在分析研究中，组蛋白去乙酰化酶（HDAC）抑制剂治疗最强烈地诱导了 miR-183。强制表达 miR-183 会触发细胞凋亡，并抑制体外无锚定集落形成和小鼠异种移植物生长。此外，miR-183 诱导的机制被发现有助于 HDAC 抑制剂诱导的细胞死亡表型。为了确定参与 miR-183 转录调控的 HDAC(s)，实验表明 HDAC2 耗竭诱导了 miR-183。HDAC2 过表达降低了 miR-183 水平，并抵消了 HDAC2 耗竭或 HDAC 抑制剂处理引起的诱导。发现 MYCN 将 HDAC2 招募到同一复合物中，作用于 miR-183 启动子，HDAC2 耗竭增强了与启动子相关的组蛋白 H4 泛乙酰化，表明转录激活之前发生了表观遗传变化。这些数据揭示了 miR-183 在神经母细胞瘤中的肿瘤抑制特性，这些特性受到 MYCN 和 HDAC2 的共同抑制，并提出了一种绕过 MYCN 功能的新方法。
