YAP in tumorigenesis: Friend or foe?
Authors: Sushun Liu, Qing Pang, Jingyao Zhang, Chang Liu
Journal: Journal of Hepatology (2015)

YAP activation is an early event and a potential therapeutic target in liver cancer developmentJournal of HepatologyVol. 61Issue 5PreviewAlthough the growth suppressing Hippo pathway has been implicated in hepatocellular carcinoma (HCC) pathogenesis, it is unknown at which stage of hepatocarcinogenesis its dysregulation occurs. We investigated in rat and human preneoplastic lesions whether overexpression of the transcriptional co-activator Yes-associated protein (YAP) is an early event. Full-Text PDF Reply to: “YAP in tumorigenesis: Friend or foe?”Journal of HepatologyVol. 62Issue 6PreviewWe read with interest the letter by Liu et al., commenting on our study about the activation of YAP in early stages of hepatocellular carcinoma (HCC) development and its potential role as a therapeutic target in liver cancer development, recently published in Journal of Hepatology [1]. In their letter, Liu et al. cite some papers and reviews proposing an oncosuppressive role of YAP. Full-Text PDF Open Access We read with great interest the recent Journal of Hepatology article published by Perra et al. [[1]Perra A. Kowalik M.A. Ghiso E. Ledda-Columbano G.M. Di Tommaso L. Angioni M.M. et al.YAP activation is an early event and a potential therapeutic target in liver cancer development.J Hepatol. 2014; 61: 1088-1096Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar]. The authors proved that yes-associated protein (YAP) accumulated in early preneoplastic lesions and oval cells in the resistant-hepatocyte rat model and in early dysplastic nodules and adenomas in human, respectively. Moreover, verteporfin which disrupted the formation of YAP-TEAD complex was proven to decrease the accumulation of YAP. It seemed that YAP was a pernicious factor in an experimental model or in humans with tumors. Thus, they highlighted the synchronous relationship between YAP and liver tumorigenesis and the function of YAP used as a therapeutic target in liver cancer. We want to point out that in contradiction to the data by Perra et al., Wang et al. [[2]Wang H. Du Y.C. Zhou X.J. Liu H. Tang S.C. The dual functions of YAP-1 to promote and inhibit cell growth in human malignancy.Cancer Metastasis Rev. 2014; 33: 173-181Crossref PubMed Scopus (43) Google Scholar] showed that YAP could inhibit the growth of human malignant cells via apoptosis by the activation of the p73 pathway. In addition, PML is another tumor suppressor pathway in collaboration with YAP, it can interact with YAP-1 and enhance the stabilization of YAP-1 [[3]Lapi E. Di Agostino S. Donzelli S. Gal H. Domany E. Rechavi G. et al.PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop.Mol Cell. 2008; 32: 803-814Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar]. In another article, Bertini et al. [[4]Bertini E. Oka T. Sudol M. Strano S. Blandino G. YAP: at the crossroad between transformation and tumor suppression.Cell Cycle. 2014; 8: 49-57Crossref Scopus (94) Google Scholar] also demonstrated that YAP-1 associated with p73 and increased the stability of p73 to induce apoptosis involved in YAP. Moreover, research conducted by Strano et al. [[5]Strano S. Munarriz E. Rossi M. Castagnoli L. Shaul Y. Sacchi A. et al.Physical interaction with Yes-associated protein enhances p73 transcriptional activity.J Biol Chem. 2001; 276: 15164-15173Crossref PubMed Scopus (352) Google Scholar] revealed that the WW domains of YAP interacted only with the member of the p53 family which had a PPXY motif. The principle of sequence-specific protein–protein interaction determined that p73γ, a p73 isoform, could not interact with YAP, although the overexpression of YAP increased the p73α transcription. In conclusion, YAP has the dual function of inhibition and promotion in oncogenesis, depending on the specific tissues or cancer types. In addition, it is necessary to study the molecular partners related to YAP before YAP targeting therapy is further developed. In addition to the relationship between YAP and the growth of cancer, another report investigated the relationship between YAP and chemosensitivity in hepatocellular carcinoma cells. Bai et al. [[6]Bai N. Zhang C. Liang N. Zhang Z. Chang A. Yin J. et al.Yes-associated protein (YAP) increases chemosensitivity of hepatocellular carcinoma cells by modulation of p53.Cancer Biol Ther. 2013; 14: 511-520Crossref PubMed Scopus (48) Google Scholar] found that YAP increased chemosensitivity of HepG2 cells by modulating p53 and both TEAD and WW domains were necessary for the function of p53 mediated by YAP. Furthermore, p53 could positively feedback to control YAP expression via interacting with the promoter of YAP. Moreover, the articles by Ehsanian et al. [[7]Ehsanian R. Brown M. Lu H. Yang X.P. Pattatheyil A. Yan B. et al.YAP dysregulation by phosphorylation or DeltaNp63-mediated gene repression promotes proliferation, survival and migration in head and neck cancer subsets.Oncogene. 2010; 29: 6160-6171Crossref PubMed Scopus (84) Google Scholar] and Yuan et al. [[8]Yuan M. Tomlinson V. Lara R. Holliday D. Chelala C. Harada T. et al.Yes-associated protein (YAP) functions as a tumor suppressor in breast.Cell Death Differ. 2008; 15: 1752-1759Crossref PubMed Scopus (247) Google Scholar] pointed out that YAP acted as a tumor suppressor in head and neck cancer and breast cancer. A further study found that YAP-1 had the ability to promote anoikis and inhibit the metastasis in breast cancer [[9]Yu S.J. Hu J.Y. Kuang X.Y. Luo J.M. Hou Y.F. Di G.H. et al.MicroRNA-200a promotes anoikis resistance and metastasis by targeting YAP1 in human breast cancer.Clin Cancer Res. 2013; 19: 1389-1399Crossref PubMed Scopus (115) Google Scholar]. In conclusion, YAP can produce both beneficial and detrimental effects in the growth of malignant cells. It has been confirmed to play contradictory roles in tumorigenesis. Therefore, more experimental and clinical research is paramount to explore the complicated relationship between YAP and tumorigenesis before YAP has been considered as a novel therapeutic target. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.