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EMBO Reports:浙江澳门永利赵斌实验组报道Hippo信号通路促进癌症转移的新转录调控机制

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摘要 : 2018年4月17日,欧洲分子生物学杂志《EMBO Reports》杂志上在线发表了浙江澳门永利生命科学研究院 赵斌实验室题为“PRDM4 mediates YAP-induced cell invasion by activating leukocyte-specific integrinb2 expression”的论文

2018年4月17日,欧洲分子生物学杂志《EMBO Reports》杂志上在线发表了浙江澳门永利生命科学研究院 赵斌实验室题为“PRDM4 mediates YAP-induced cell invasion by activating leukocyte-specific integrinb2 expression”的论文,研究论文同时被选为该杂志六月的封面文章。博士研究生刘欢、代晓明和曹晓磊是本文共同第一作者,赵斌教授是本文通讯作者。

Hippo信号转导通路在器官大小调控、癌症发生、组织再生、以及干细胞的功能上发挥重要作用。其中重要的效应分子YAP作为转录辅激活因子,其异常激活能够促进肿瘤的起始和发展,然而YAP促进细胞入侵和肿瘤转移的机制尚不清楚。

本研究发现YAP 促进白细胞特异性整合素亚基ITGB2 在癌细胞中表达,从而使癌细胞模拟白细胞跨内皮迁移,促进癌细胞入侵和肿瘤转移。而YAP作为转录辅激活因子,通过结合转录因子发挥转录激活功能。YAP调控ITGB2的表达同时依赖于YAP的WW结构域以及 TEAD转录因子。通过串联亲和纯化质谱分析和转录因子文库筛选两种方法发现PRDM4是YAP的WW结构域结合的新转录因子。PRDM4、TEAD、YAP形成三元复合物,并结合在ITGB2的启动子上协同促进ITGB2表达。PRDM4参与YAP诱导的跨内皮迁移和肿瘤形成。进一步分析癌症基因组图谱数据集(Cancer Genome Atlas (TCGA) dataset)发现,与正常组织相比,PRDM4 和ITGB2的mRNA水平和YAP的活性在转移性前列腺癌中明显上升并呈现正相关性。

本项研究发现了Hippo信号通路促进癌症转移的新转录调控机制,并提示YAP-PRDM4 复合物是癌症治疗的新的潜在靶点。

EMBO Reports:浙江澳门永利赵斌实验组报道Hippo信号通路促进癌症转移的新转录调控机制
图注:PRDM4、TEAD、YAP形成三元复合物协同诱导白细胞特异性整合素亚基 ITGB2 在癌细胞中表达,从而使癌细胞模拟白细胞跨内皮迁移,促进癌细胞入侵和肿瘤转移。

原文链接:

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

原文摘要:

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.

DOI:10.15252/embr.201745180

作者:赵斌 点击:

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