Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):E2441-50. doi: 10.1073/pnas.1212021109. Epub 2012 Aug 13.
The transcriptional coactivator Yes-associated protein (YAP) is a major regulator of organ size and proliferation in vertebrates. As such, YAP can act as an oncogene in several tissue types if its activity is increased aberrantly. Although no activating mutations in the yap1 gene have been identified in human cancer, yap1 is located on the 11q22 amplicon, which is amplified in several human tumors. In addition, mutations or epigenetic silencing of members of the Hippo pathway, which represses YAP function, have been identified in human cancers. Here we demonstrate that, in addition to increasing tumor growth, increased YAP activity is potently prometastatic in breast cancer and melanoma cells. Using a Luminex-based approach to multiplex in vivo assays, we determined that the domain of YAP that interacts with the TEAD/TEF family of transcription factors but not the WW domains or PDZ-binding motif, is essential for YAP-mediated tumor growth and metastasis. We further demonstrate that, through its TEAD-interaction domain, YAP enhances multiple processes known to be important for tumor progression and metastasis, including cellular proliferation, transformation, migration, and invasion. Finally, we found that the metastatic potential of breast cancer and melanoma cells is strongly correlated with increased TEAD transcriptional activity. Together, our results suggest that increased YAP/TEAD activity plays a causal role in cancer progression and metastasis.
转录共激活因子 Yes 相关蛋白（YAP）是脊椎动物器官大小和增殖的主要调节因子。因此，如果 YAP 的活性异常增加，它可以在几种组织类型中充当致癌基因。尽管在人类癌症中没有发现 yap1 基因的激活突变，但 yap1 位于 11q22 扩增子上，该扩增子在几种人类肿瘤中被扩增。此外，已经在人类癌症中鉴定出 Hippo 通路成员的突变或表观遗传沉默，该通路抑制 YAP 功能。在这里，我们证明除了增加肿瘤生长外，YAP 活性的增加在乳腺癌和黑色素瘤细胞中具有很强的促转移作用。我们使用基于 Luminex 的方法进行多重体内测定，确定与 TEAD/TEF 转录因子家族相互作用但不与 WW 结构域或 PDZ 结合基序相互作用的 YAP 结构域对于 YAP 介导的肿瘤生长和转移是必需的。我们进一步证明，通过其 TEAD 相互作用结构域，YAP 增强了已知对肿瘤进展和转移很重要的多个过程，包括细胞增殖、转化、迁移和侵袭。最后，我们发现乳腺癌和黑色素瘤细胞的转移潜力与 TEAD 转录活性的增加密切相关。总之，我们的研究结果表明，YAP/TEAD 活性的增加在癌症进展和转移中起因果作用。
