VGLL4 targets a TCF4-TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer.
VGLL4 targets a TCF4-TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer.
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VGLL4 靶向 TCF4-TEAD4 复合物共同调节结直肠癌中的 Wnt 和 Hippo 信号传导
DOI：
10.1038/ncomms14058
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发表时间：
2017-01-04
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
多条信号通路的协同协同调节对组织稳态和肿瘤发生至关重要。在这里，我们报道了VGLL4，一个先前发现的YAP拮抗剂，也是Wnt/β-catenin信号的调节者。VGLL4在临床结直肠癌组织中的表达显著下调，与患者的生存率呈正相关，与Wnt靶基因在结直肠癌中的表达呈负相关。VGLL4基因敲除促进了结直肠癌细胞的增殖和肿瘤形成。一种设计的模拟VGLL4功能的多肽有效地抑制了新生小鼠模型中的CRC进展。机制上，TEAD4与TCF4结合形成复合体，共同结合靶基因。VGLL4靶向TEAD4-TCF4复合体，干扰TEAD4和TCF4之间的功能相互作用，抑制TCF4的反式激活。总之，我们的研究表明，Wnt/β-catenin和Hippo-YAP信号在转录因子水平上直接相连，VGLL4可以靶向TEAD4-TCF4复合体来共同调节这两条途径。Wnt/β-catenin和YAP信号通路在癌症中起着重要作用。在这里，作者表明，VGLL4，一个已知的YAP拮抗剂，也通过靶向Tead-β-TCF4复合体负向调节Wnt/DNAcenin信号，从而抑制结直肠癌的生长。
Concerted co-regulation of multiple signalling pathways is crucial for tissue homoeostasis and tumorigenesis. Here we report that VGLL4, a previously identified YAP antagonist, also functions as a regulator of Wnt/β-catenin signalling. The expression of VGLL4 is significantly downregulated in clinical colorectal carcinoma (CRC) specimens, positively associated with patient survival rate, and inversely correlated with the expression of Wnt target genes in CRCs. Knockdown of VGLL4 enhances proliferation and tumour formation of CRC cells. A designed peptide mimicking the function of VGLL4 effectively inhibits CRC progression in a de novo mouse model. Mechanistically, TEAD4 associates with TCF4 to form a complex and cobind target genes. VGLL4 targets this TEAD4–TCF4 complex to interfere the functional interplay between TEAD4 and TCF4, suppressing the transactivation of TCF4. Collectively, our study indicates that Wnt/β-catenin and Hippo-YAP signalling are directly linked at transcription factor-level, and VGLL4 can target a TEAD4–TCF4 complex to co-regulate both pathways. The Wnt/β-catenin and YAP signaling pathways have fundamental roles in cancer. Here, the authors show that VGLL4, a known YAP antagonist, also negatively regulates Wnt/β-catenin signaling by targeting TEAD-DNA-TCF4 complex, thereby inhibiting colorectal cancer growth.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1126/science.1199010
发表时间：
2011-04-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Heallen T;Zhang M;Wang J;Bonilla-Claudio M;Klysik E;Johnson RL;Martin JF
通讯作者：
Martin JF
影响因子：
11.4
作者：
Lau, Allison N.;Curtis, Stephen J.;Kim, Carla F.
通讯作者：
Kim, Carla F.
模拟 VGLL4 功能的肽作为 YAP 拮抗剂治疗胃癌
影响因子：
50.3
作者：
Jiao, Shi;Wang, Huizhen;Zhou, Zhaocai
通讯作者：
Zhou, Zhaocai
影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia