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Elucidation of the mechanisms of the Hippo-YAP pathway in organ size control and cancer

  • Author(s): Tumaneng, Karen A.
  • et al.
Abstract

The Hippo pathway is a highly conserved signaling pathway that plays a crucial role in the regulation of organ size. A major downstream target of the Hippo pathway in mammals is the Yes-associated protein (YAP), which functions as a transcription co-activator. The importance of YAP in organ size control and cancer development has been established by several studies. The underlying molecular mechanisms, however, have not been elucidated. Herein, we delineate the mechanisms through which YAP regulates organ size and contributes to cancer. Organ development is a complex process that is governed by the interplay of signaling pathways that play crucial roles in the regulation of cell growth, cell proliferation, and cell death. The Hippo pathway has emerged as a key regulator of organ size by controlling cell number via modulation of cell proliferation and cell death. The highly conserved mechanistic target of rapamycin (mTOR) is another pathway that has a central role in organ size control. mTOR regulates organ size by promoting cell growth, thereby increasing cell size. Given that cell growth is required for cell division and hence proliferation, it has been speculated that the functions of the Hippo and mTOR pathways are coordinated under physiological conditions. Here, we demonstrate that YAP induces the activation of the mTOR pathway by suppressing the expression of the tumor suppressor PTEN, a key antagonist of PI3K and a well established upstream negative regulator of the mTOR pathway. YAP inhibits PTEN by directly inducing the miR-29 microRNAs, which bind the 3' untranslated region of PTEN to suppress PTEN translation. Importantly, we show that PI3K-mTOR is a pathway modulated by YAP to regulate tissue growth and hyperplasia. These findings provide a basis for the coordination of the Hippo and mTOR pathways in organ size control, and reveal an important mechanism through which YAP regulates growth. As a crucial regulator of growth and proliferation, YAP acts as a potent inducer of tumorigenesis and metastasis. Here, we demonstrate that knockdown of YAP alone is sufficient to reverse cancer phenotypes, highlighting a very important role of YAP in cancer. We provide the molecular basis of this regulation and demonstrate that YAP regulates the Zeb2 transcriptional repressor to induce a cellular program called epithelial-mesenchymal transition (EMT), which is required for tumor infiltration and cancer metastasis. Knockdown of Zeb2 is sufficient to abolish YAP-induced cancer phenotypes, indicating that Zeb2 is an important mediator of YAP in cancer. Ultimately, we found that Zeb2 is a direct target gene of YAP. Taken together, our studies provide insights into how the Hippo-YAP pathway regulates growth and promotes cancer, and reveal potential therapeutic avenues for diseases with Hippo pathway mutations

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