title: The Hippo pathway transcriptional co-activator, YAP, confers resistance to cisplatin in human oral squamous cell carcinoma.
abstract: Cisplatin (CDDP) is widely used to treat oral squamous cell carcinoma (OSCC), however, many patients exhibit acquired drug resistance. Yes-associated protein (YAP) is a transcriptional co-activator of the Hippo pathway that regulates organ size and promotes cell proliferation. YAP overexpression correlates with epithelial-mesenchymal transition and nodal metastasis, resulting in anti-tubulin drug resistance. Whether YAP overexpression is the cause of CDDP resistance in cancer cells is unclear, therefore, we investigated the correlation between YAP expression and CDDP sensitivity. We established three CDDP-resistant cell lines (OSC-19-R, SCCKN-R and HSC-3-R) from the OSCC parental cell lines. We also examined the expression levels of ATP7B, GST-π and ERCC1, which are strongly associated with CDDP resistance, and Hippo pathway-related proteins by western blotting. Using immunocytochemistry, we examined the cellular localization of YAP. Additionally, following knockdown of YAP using short interfering RNAs (siRNAs), we analyzed changes in sensitivity to CDDP. Compared with parental OSC-19 cells, OSC-19-R cells were obviously larger. Expression levels of YAP were not significantly different between OSC-19 and OSC-19-R. However, expression levels of phosphorylated YAP in OSC-19-R were decreased. We observed translocation of YAP from the cytoplasm to the nucleus in OSC-19-R cells. Knockdown of YAP using siRNAs revealed that sensitivity to CDDP was significantly increased. Translocation of YAP correlated with the acquisition of CDDP resistance. YAP could be a new therapeutic target for the treatment of patients with cancer that are resistant to CDDP.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Yoshikawa
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Noguchi
authors.affiliation: Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Nakano
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Yamamura
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Takaoka
authors.affiliation: Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hashimoto-Tamaoki
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kishimoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009062:Mouth Neoplasms / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D002945:Cisplatin