Wang Bo, Shao Wenyu, Shi Yue, Liao Jiongbo, Chen Xiaojun, Wang Chao
Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University Shanghai, People's Republic of China.
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases Shanghai 200011, People's Republic of China.
Am J Cancer Res. 2020 Apr 1;10(4):1207-1217. eCollection 2020.
Yes-associated protein (YAP or YAP1) has been proposed to function as an oncogene in most cancers, with nuclear localization of YAP1 correlating with poor prognosis. Photosensitizer Verteporfin has been proven as an inhibitor of YAP1 through preventing the combination of YAP1 with TEA domain transcription factor (TEAD). We showed previously that the total and phospho-levels of YAP1 were related to the clinical characteristics and outcomes in endometrial cancer (EC) patients, and that YAP1 promoted the proliferation and metastasis of EC cells in vitro cell line studies and in animal models. We also reported that Verteporfin inhibited cell growth and induced cell death through inhibiting YAP1 in EC in our previous study. However, the mechanism of how Verteporfin inhibits the function of YAP1 remains unclear. In this study, we analyzed the global effects of Verteporfin on cell function by using Reverse Phase Protein Arrays (RPPA) and Ingenuity Pathway Analysis (IPA). Furthermore, we demonstrated that Verteporfin induced the SUMOylation of YAP1 for the first time. Interestingly, we found that the SUMOylation of YAP1 was regulated by YAP1 phosphorylation. Together, our study revealed a novel mechanism by which Verteporfin inhibits the function of YAP1 through regulating YAP1 SUMOylation. Our study may provide a rationale for the clinical use of Verteporfin in endometrial cancer by targeting YAP1.
Yes相关蛋白（YAP或YAP1）在大多数癌症中被认为起着癌基因的作用，YAP1的核定位与预后不良相关。光敏剂维替泊芬已被证明是YAP1的抑制剂，它通过阻止YAP1与TEA结构域转录因子（TEAD）结合来发挥作用。我们之前表明，YAP1的总量和磷酸化水平与子宫内膜癌（EC）患者的临床特征及预后相关，并且在体外细胞系研究和动物模型中，YAP1促进了EC细胞的增殖和转移。我们还在之前的研究中报道，维替泊芬通过抑制EC中的YAP1来抑制细胞生长并诱导细胞死亡。然而，维替泊芬抑制YAP1功能的机制仍不清楚。在本研究中，我们通过使用反向蛋白质阵列（RPPA）和 Ingenuity通路分析（IPA）来分析维替泊芬对细胞功能的整体影响。此外，我们首次证明维替泊芬诱导了YAP1的SUMO化。有趣的是，我们发现YAP1的SUMO化受YAP1磷酸化调节。总之，我们的研究揭示了一种新机制，即维替泊芬通过调节YAP1的SUMO化来抑制YAP1的功能。我们的研究可能为维替泊芬在子宫内膜癌中靶向YAP1的临床应用提供理论依据。
