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Bin Zhao’s Laboratory reported a noveltranscriptionalmechanism of the Hippo pathwayregulating cell invasion and metastasis


Dr. Bin Zhao’s group published a research article on EMBO reports online on April 17th 2018 with the title “PRDM4 mediates YAP-induced cell invasion byactivating leukocyte-specific integrin b2 expression”. And this research is selected as cover story on issue 6 of EMBO reports.Dr. Bin Zhao is the corresponding author and graduate studentsHuan Liu, Xiaoming Dai, and Xiaolei Cao areco-first authors.

The Hippo tumor suppressor pathway plays important roles in organ size control, tumorigenesis, tissue regeneration, and stem cell self-renewal. YAP is a key effector of Hippo pathway and its deregulation stronglypromotes cancer initiation and progression. However, the mechanismsby which YAP promotes cell invasion and metastasis arenot fully understood.

In this study, Dr. Bin Zhao’s group reported that YAP induces leukocyte-specificintegrin b2(ITGB2) expression in cancer cells, therebypromoting cell invasion through the endothelium in a mannermimicking leukocytes.As a transcriptional co-activator,YAP activates gene expression through interaction with transcription factors. In this report, it was found that YAP induced-ITGB2 expression depends on both TEAD transcription factors and YAP WW domains. Through two independent approaches, tandem affinity purification coupled with mass spectrometry ,and luciferase reporter assay based screening of a human transcription factor library, PR/SET domain4 (PRDM4) was found to be a novel transcription factor partner of YAP. PRDM4 interacts with YAP through PPXY motif-WW domain interactions. PRDM4, YAP and TEAD form a heterotrimeric complex and directly bound to ITGB2 promoterto activate ITGB2 expression cooperatively. PRDM4 contributed to YAP-induced cell invasion and tumorigenesis. Moreover, analysis of Cancer GenomeAtlas (TCGA) datasets revealed that PRDM4 and ITGB2 mRNA levels as well as YAP activity significantly increased and evidently correlated compared with normal tissue.

These findings revealanoveltranscriptionalmechanism of the Hippo pathwayin regulation of cell invasion and metastasis.YAP-PRDM4 complex could be a potential target for therapeuticintervention.

Figure legend. PRDM4, YAP and TEAD form a heterotrimeric complex toinduce leukocyte-specific integrin β2 (ITGB2) expression cooperatively, and thus promote cancer cell invasion through endothelium in a manner mimicking leukocytes.