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.