PRDM4 mediates YAP-induced cell invasion by activating leukocyte-specific integrin β2 expression
PRDM4 mediates YAP-induced cell invasion by activating leukocyte-specific integrin β2 expression
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PRDM4 通过激活白细胞特异性整合素 β2 表达介导 YAP 诱导的细胞侵袭
DOI：
10.15252/embr.201745180
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发表时间：
2018-06-01
期刊：
影响因子：
7.7
通讯作者：
Zhao, Bin
中科院分区：
文献类型：
--
作者：
Liu, Huan;Dai, Xiaoming;Zhao, Bin
Yes 相关蛋白 (YAP) 是一种转录共激活因子，也是 Hippo 通路的主要效应子，可促进细胞增殖和干细胞性，同时抑制细胞凋亡。 YAP 在器官大小控制中发挥着核心作用，其失调会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。在此，我们报道 YAP 诱导癌细胞中白细胞特异性整合素 2 (ITGB2) 表达，从而以模仿白细胞的方式促进细胞通过内皮侵袭。通过独立的生化纯化和功能筛选，我们进一步鉴定了PR/SET结构域4（PRDM4）作为与YAP的WW结构域相互作用介导ITGB2表达和细胞侵袭的转录因子。一致地，ITGB2 和 PRDM4 mRNA 水平在转移性前列腺癌中显着增加。此外，PRDM4可能通过介导其他YAP靶基因的表达而促进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来促进细胞侵袭，并将 PRDM4 确定为 YAP 靶点的新型转录因子。
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 integrin 2 (ITGB2) 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 ITGB2 expression and cell invasion. Consistently, ITGB2 and PRDM4 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.