PRDM4 mediates YAP‐induced cell invasion by activating leukocyte‐specific integrin β2 expression

• Published in: EMBO reports Vol. 19; no. 6
• Main Authors: Liu, Huan, Dai, Xiaoming, Cao, Xiaolei, Yan, Huan, Ji, Xinyan, Zhang, Haitao, Shen, Shuying, Si, Yuan, Zhang, Hailong, Chen, Jianfeng, Li, Li, Zhao, Jonathan C, Yu, Jindan, Feng, Xin‐Hua, Zhao, Bin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2018; Springer Nature B.V; John Wiley and Sons Inc
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - physiology; Animals; Apoptosis; Cancer; CD18 Antigens - metabolism; Cell growth; cell invasion; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Deregulation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; EMBO03; EMBO37; Endothelium; Gene expression; Genes; Hippo pathway; Humans; ITGB2; Kinases; Leukocytes; Male; Metastases; Mice; Mimicry; Neoplasm Invasiveness; Phosphoproteins - genetics; Phosphoproteins - physiology; PRDM4; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; Scientific Report; Scientific Reports; Transcription activation; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumorigenesis; Yes-associated protein; Hippo pathway; yes‐associated protein; cell invasion; PRDM4; ITGB2
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.15252/embr.201745180

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 β2 ( 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. Synopsis Yes‐associated protein (YAP) is a transcriptional co‐activator and major effector of the Hippo pathway, promoting cell proliferation and stemness. YAP interacts with PRDM4, thereby promoting transendothelial invasion of cancer cells by inducing expression of the leukocyte‐specific integrin ITGB2. PR/SET domain 4 (PRDM4) interacts with YAP to promote transcriptional activation of target genes. PRDM4 and TEAD co‐ordinately mediate the activation of the YAP target gene ITGB2. YAP‐induced ITGB2 expression promotes cancer cell invasion in a manner mimicking leukocytes. Graphical Abstract Yes‐associated protein (YAP) is a transcriptional co‐activator and major effector of the Hippo pathway, promoting cell proliferation and stemness. YAP interacts with PRDM4, thereby promoting transendothelial invasion of cancer cells by inducing expression of the leukocyte‐specific integrin ITGB2.