Gene Regulation Stem Cells and Cancer Program, Center for Genomic Regulation (CRG), Dr. Aiguader 88, 08003 Barcelona, Spain.
Cell Rep. 2013 Jun 27;3(6):2021-32. doi: 10.1016/j.celrep.2013.05.024. Epub 2013 Jun 13.
Polo-like kinase 1 (PLK1) is a key regulator of cell division and is overexpressed in many types of human cancers. Compared to its well-characterized role in mitosis, little is known about PLK1 functions in interphase. Here, we report that PLK1 mediates estrogen receptor (ER)-regulated gene transcription in human breast cancer cells. PLK1 interacts with ER and is recruited to ER cis-elements on chromatin. PLK1-coactivated genes included classical ER target genes such as Ps2, Wisp2, and Serpina3 and were enriched in developmental and tumor-suppressive functions. Performing large-scale phosphoproteomics of estradiol-treated MCF7 cells in the presence or absence of the specific PLK1 inhibitor BI2536, we identified several PLK1 end targets involved in transcription, including the histone H3K4 trimethylase MLL2, the function of which on ER target genes was impaired by PLK1 inhibition. Our results propose a mechanism for the tumor-suppressive role of PLK1 in mammals as an interphase transcriptional regulator.
丝氨酸苏氨酸激酶 1（PLK1）是细胞分裂的关键调节因子，在许多人类癌症中过度表达。与它在有丝分裂中得到充分研究的作用相比，人们对 PLK1 在间期的功能知之甚少。在这里，我们报告 PLK1 介导人类乳腺癌细胞中雌激素受体（ER）调节的基因转录。PLK1 与 ER 相互作用，并被招募到染色质上的 ER 顺式元件。PLK1 共激活的基因包括经典的 ER 靶基因，如 Ps2、Wisp2 和 Serpina3，并富集在发育和肿瘤抑制功能中。在存在或不存在特异性 PLK1 抑制剂 BI2536 的情况下，对用雌二醇处理的 MCF7 细胞进行大规模磷酸化蛋白质组学分析，我们鉴定了几个参与转录的 PLK1 终靶标，包括组蛋白 H3K4 三甲基转移酶 MLL2，其在 ER 靶基因上的功能被 PLK1 抑制所损害。我们的结果提出了 PLK1 在哺乳动物中作为间期转录调节剂的肿瘤抑制作用的机制。
