Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Mol Cell Biol. 2013 Aug;33(15):2879-90. doi: 10.1128/MCB.01620-12. Epub 2013 May 28.
Inappropriate activation of the transcription factors STAT3 and STAT5 has been shown to drive cancer pathogenesis through dysregulation of genes involved in cell survival, growth, and differentiation. Although STAT3 and STAT5 are structurally related, they can have opposite effects on key genes, including BCL6. BCL6, a transcriptional repressor, has been shown to be oncogenic in diffuse large B cell lymphoma. BCL6 also plays an important role in breast cancer pathogenesis, a disease in which STAT3 and STAT5 can be activated individually or concomitantly. To determine the mechanism by which these oncogenic transcription factors regulate BCL6 transcription, we analyzed their effects at the levels of chromatin and gene expression. We found that STAT3 increases expression of BCL6 and enhances recruitment of RNA polymerase II phosphorylated at a site associated with transcriptional initiation. STAT5, in contrast, represses BCL6 expression below basal levels and decreases the association of RNA polymerase II at the gene. Furthermore, the repression mediated by STAT5 is dominant over STAT3-mediated induction. STAT5 exerts this effect by displacing STAT3 from one of the two regulatory regions to which it binds. These findings may underlie the divergent biology of breast cancers containing activated STAT3 alone or in conjunction with activated STAT5.
转录因子 STAT3 和 STAT5 的异常激活已被证明通过失调参与细胞存活、生长和分化的基因来驱动癌症发病机制。尽管 STAT3 和 STAT5 在结构上相关，但它们对关键基因（包括 BCL6）可能具有相反的影响。BCL6 是一种转录抑制剂，已被证明在弥漫性大 B 细胞淋巴瘤中具有致癌性。BCL6 还在乳腺癌发病机制中发挥着重要作用，在这种疾病中，STAT3 和 STAT5 可以单独或同时被激活。为了确定这些致癌转录因子调节 BCL6 转录的机制，我们分析了它们在染色质和基因表达水平上的作用。我们发现 STAT3 增加了 BCL6 的表达，并增强了与转录起始相关的磷酸化 RNA 聚合酶 II 的募集。相比之下，STAT5 抑制 BCL6 的表达，使其低于基础水平，并减少基因上 RNA 聚合酶 II 的结合。此外，STAT5 介导的抑制作用超过了 STAT3 介导的诱导作用。STAT5 通过将 STAT3 从其结合的两个调节区域之一中置换出来发挥这种作用。这些发现可能是含有单独激活的 STAT3 或与激活的 STAT5 结合的乳腺癌具有不同生物学特性的基础。
