Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, China.
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
EMBO Rep. 2018 Jun;19(6). doi: 10.15252/embr.201745180. Epub 2018 Apr 17.
Yes-associated protein (YAP) is a transcriptional co-activator and a major effector of the Hippo pathway that promotes cell proliferation and stemness, while inhibiting apoptosis. YAP plays a central role in organ size control, and its deregulation strongly promotes cancer initiation and progression. However, the mechanisms by which YAP promotes cell invasion and metastasis are not fully understood. Here, we report that YAP induces leukocyte-specific () expression in cancer cells, thereby promoting cell invasion through the endothelium in a manner mimicking leukocytes. Through independent biochemical purification and a functional screen, we further identified PR/SET domain 4 (PRDM4) as a transcription factor interacting with the WW domains of YAP to mediate expression and cell invasion. Consistently, and mRNA levels are significantly increased in metastatic prostate cancer. In addition, PRDM4 contributes to YAP-induced tumorigenesis possibly via mediating the expression of other YAP target genes. Our results demonstrate that YAP promotes cell invasion by inducing leukocyte-specific integrin expression, and identify PRDM4 as a novel transcription factor for YAP targets.
Yes 相关蛋白 (YAP) 是 Hippo 通路的转录共激活因子和主要效应因子，它促进细胞增殖和干性，同时抑制细胞凋亡。YAP 在器官大小控制中发挥核心作用，其失调强烈促进癌症的发生和进展。然而，YAP 促进细胞侵袭和转移的机制尚不完全清楚。在这里，我们报告 YAP 在癌细胞中诱导白细胞特异性 () 表达，从而通过模仿白细胞的方式通过内皮促进细胞侵袭。通过独立的生化纯化和功能筛选，我们进一步鉴定 PR/SET 结构域 4 (PRDM4) 作为与 YAP 的 WW 结构域相互作用的转录因子，介导 表达和细胞侵袭。一致地，转移性前列腺癌中 和 mRNA 水平显著增加。此外，PRDM4 通过介导其他 YAP 靶基因的表达可能有助于 YAP 诱导的肿瘤发生。我们的结果表明，YAP 通过诱导白细胞特异性整合素表达促进细胞侵袭，并鉴定 PRDM4 为 YAP 靶标的新型转录因子。
