Verteporfin inhibits YAP function through up-regulating 14-3-3σ sequestering YAP in the cytoplasm

Chao Wang, Xiaoyong Zhu, Weiwei Feng, Yinhua Yu, Kangjin Jeong, Wei Guo, Yiling Lu, Gordon B. Mills

    Research output: Contribution to journalArticlepeer-review

    74 Scopus citations

    Abstract

    Yes-associated protein (YAP), the central mediator of Hippo pathway, not only regulates a diversity of cellular processes during development but also plays a pivotal role in tumorigenesis. YAP is overexpressed in many types of human cancers with its expression level being associated with patient outcomes. Thus, inhibiting YAP function could provide a novel therapeutic approach. Verteporfin, a photosensitizer, which has been used in photodynamic therapy (PDT), was recently identified as an inhibitor of the interaction of YAP with TEAD, which, in turn, blocks transcriptional activation of targets downstream of YAP. However, the mechanism by which Verteporfin inhibits YAP activity remains to be elucidated. We demonstrate that overexpression of YAP stimulates cell proliferation whereas knocking down YAP or treating cells with Verteporfin inhibited cell proliferation, even in the presence of growth factors. Protoporphyrin IX, another photosensitizer, did not have similar activity demonstrating specificity to Verteporfin. Verteporfin induced sequestration of YAP in cytoplasm through increasing levels of 14-3-3σ, a YAP chaperon protein that retains YAP in cytoplasm and targets it for degradation in the proteosome. Interestingly, while knockdown of YAP had no effect on the ability of Verteporfin to induce 14-3-3σ, p53 is required for this effect of Verteporfin. This provides potential approaches to select patients likely to benefit from Verteporfin.

    Original languageEnglish (US)
    Pages (from-to)27-37
    Number of pages11
    JournalAmerican Journal of Cancer Research
    Volume6
    Issue number1
    StatePublished - 2016

    Keywords

    • 14-3-3σ
    • Endometrial cancer
    • Verteporfin
    • YAP

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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