Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile.
Programa de Genética Humana, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile.
Genes (Basel). 2022 Jan 26;13(2):234. doi: 10.3390/genes13020234.
Transcriptional coactivators play a key role in RNA polymerase II transcription and gene regulation. One of the most important transcriptional coactivators is the Mediator (MED) complex, which is an evolutionary conserved large multiprotein complex. MED transduces the signal between DNA-bound transcriptional activators (gene-specific transcription factors) to the RNA polymerase II transcription machinery to activate transcription. It is known that MED plays an essential role in ER-mediated gene expression mainly through the MED1 subunit, since estrogen receptor (ER) can interact with MED1 by specific protein-protein interactions; therefore, MED1 plays a fundamental role in ER-positive breast cancer (BC) etiology. Additionally, other MED subunits also play a role in BC etiology. On the other hand, microRNAs (miRNAs) are a family of small non-coding RNAs, which can regulate gene expression at the post-transcriptional level by binding in a sequence-specific fashion at the 3' UTR of the messenger RNA. The miRNAs are also important factors that influence oncogenic signaling in BC by acting as both tumor suppressors and oncogenes. Moreover, miRNAs are involved in endocrine therapy resistance of BC, specifically to tamoxifen, a drug that is used to target ER signaling. In metazoans, very little is known about the transcriptional regulation of miRNA by the MED complex and less about the transcriptional regulation of miRNAs involved in BC initiation and progression. Recently, it has been shown that MED1 is able to regulate the transcription of the ER-dependent miR-191/425 cluster promoting BC cell proliferation and migration. In this review, we will discuss the role of MED1 transcriptional coactivator in the etiology of BC and in endocrine therapy-resistance of BC and also the contribution of other MED subunits to BC development, progression and metastasis. Lastly, we identified miRNAs that potentially can regulate the expression of MED subunits.
转录共激活因子在 RNA 聚合酶 II 转录和基因调控中发挥关键作用。最重要的转录共激活因子之一是中介体（MED）复合物，它是一种进化上保守的大型多蛋白复合物。MED 将 DNA 结合转录激活因子（基因特异性转录因子）与 RNA 聚合酶 II 转录机制之间的信号转导，从而激活转录。已知 MED 在 ER 介导的基因表达中发挥重要作用，主要通过 MED1 亚基发挥作用，因为雌激素受体（ER）可以通过特定的蛋白质-蛋白质相互作用与 MED1 相互作用；因此，MED1 在 ER 阳性乳腺癌（BC）发病机制中起着基础性作用。此外，其他 MED 亚基也在 BC 发病机制中发挥作用。另一方面，微小 RNA（miRNA）是一类小的非编码 RNA，通过在信使 RNA 的 3'UTR 以序列特异性方式结合，在转录后水平调节基因表达。miRNA 也是影响 BC 致癌信号的重要因素，它们既可以作为肿瘤抑制因子，也可以作为癌基因发挥作用。此外，miRNA 参与 BC 的内分泌治疗耐药，特别是针对他莫昔芬（一种用于靶向 ER 信号的药物）。在后生动物中，关于 MED 复合物对 miRNA 的转录调控知之甚少，关于参与 BC 起始和进展的 miRNA 的转录调控知之甚少。最近已经表明，MED1 能够调节 ER 依赖性 miR-191/425 簇的转录，从而促进 BC 细胞增殖和迁移。在这篇综述中，我们将讨论 MED1 转录共激活因子在 BC 发病机制和 BC 内分泌治疗耐药中的作用，以及其他 MED 亚基对 BC 发展、进展和转移的贡献。最后，我们确定了潜在能够调节 MED 亚基表达的 miRNA。
