title: Verteporfin inhibits YAP function through up-regulating 14-3-3σ sequestering YAP in the cytoplasm.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan UniversityShanghai 200011, China; Department of Systems Biology, The University of Texas MD Anderson Cancer CenterHouston 77030, TX, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University Shanghai 200011, China.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University Shanghai 200011, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University Shanghai 200011, China.
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center Houston 77030, TX, USA.
authors.forename: Kangjin
authors.initials: K
authors.lastname: Jeong
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center Houston 77030, TX, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center Houston 77030, TX, USA.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center Houston 77030, TX, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
keywords: 14-3-3σ; Verteporfin; YAP; endometrial cancer