title: Yes-associated protein (YAP) increases chemosensitivity of hepatocellular carcinoma cells by modulation of p53.
abstract: The yes-associated protein (YAP) transcription co-activator has been reported either as an oncogene candidate or a tumor suppressor. Liver tissue chips revealed that about 51.4% human hepatocellular carcinoma (HCC) samples express YAP and 32.9% HCC samples express phosphorylated YAP. In this study, we found that chemotherapy increased YAP protein expression and nuclear translocation in HepG2 cells, as well as p53 protein expression and nuclear translocation. However, little is known about YAP functions during chemotherapy. Our results show that overexpression of YAP increases chemosensitivity of HepG2 cells during chemotherapy. Dominant negative transfection of Flag-S94A (TEAD binding domain mutant) or Flag-W1W2 (WW domain mutant) to HepG2 cells decreases p53 expression/ nuclear translocation and chemosensitivity when compared with control HepG2 cells. Furthermore, rescue transfection of Flag-5SA-S94A or Flag-5SA-W1W2, respectively to HepG2 cells regains p53 expression/nuclear translocation and chemosensitivity. These results indicate that YAP promotes chemosensitivity by modulating p53 during chemotherapy and both TEAD and WW binding domains are required for YAP-mediated p53 function. ChIP assay results also indicated that YAP binds directly to the p53 promoter to improve its expression. In addition, p53 could positively feedback YAP expression through binding to the YAP promoter. Taken together, our current data indicate that YAP functions as a tumor suppressor that enhances apoptosis by modulating p53 during chemotherapy.
authors.affiliation: Department of Immunology, School of Medicine, Nankai University, Tianjin, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Bai
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.forename: Ning
authors.initials: N
authors.lastname: Liang
authors.forename: Zhuhong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Antao
authors.initials: A
authors.lastname: Chang
authors.forename: Jing
authors.initials: J
authors.lastname: Yin
authors.forename: Zongjin
authors.initials: Z
authors.lastname: Li
authors.forename: Na
authors.initials: N
authors.lastname: Luo
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Tan
authors.forename: Na
authors.initials: N
authors.lastname: Luo
authors.forename: Yunping
authors.initials: Y
authors.lastname: Luo
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.forename: Xiru
authors.initials: X
authors.lastname: Li
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Reisfeld
authors.forename: Dwayne
authors.initials: D
authors.lastname: Stupack
authors.forename: Dan
authors.initials: D
authors.lastname: Lv
authors.forename: Chenghu
authors.initials: C
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D010750:Phosphoproteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D010750:Phosphoproteins; D012333:RNA, Messenger; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D004317:Doxorubicin
keywords: YAP; hepatocellular carcinoma; p53