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.

hsa-miR-485-5p reverses epithelial to mesenchymal transition and promotes cisplatin-induced cell death by targeting PAK1 in oral tongue squamous cell carcinoma

“…MicroRNAs (miRs) are a class of small noncoding RNAs (~22 nucleotides) that negatively regulate protein-coding gene expression by targeting mRNA degradation or translation inhibition (18–20). To further confirm whether PAK1 is regulated by microRNAs, we used the commonly used prediction algorithm, miRanda (http://www.microrna.org/microrna/home.do), to analyze the 3′ untranslated region (3′UTR) of PAK1.…”

“…Consistent with the study, we showed that overexpression of PAK1 promoted cisplatin resistance in SCC25 cells. High expression of ERCC1 and YAP are associated with cispantin resistance in locally advanced squamous cell carcinoma of the head and neck (18,33). Our results demonstrated that overexpression of PAK1 promoted ERCC1 and YAP protein expression in the SCC25 cells.…”

Loss of YAP1 defines neuroendocrine differentiation of lung tumors

“…Our survival curves in Figure (a) also showed that, among YAP1‐positive cases, the adjuvant chemotherapy group had a slightly worse prognosis than the non‐adjuvant chemotherapy group, which suggested that adverse drug reactions may exceed the beneficial effects of platinum‐based chemotherapy in YAP1‐positive high‐grade neuroendocrine tumors. Recently, YAP1 has been attracting attention as a key molecule to determine the resistance of various tumors to platinum, including NSCLC, oral cancer, cervical cancer, thyroid cancer, and ovarian cancer . Cheng et al .…”

“…Recently, YAP1 has been attracting attention as a key molecule to determine the resistance of various tumors to platinum, including NSCLC, oral cancer, cervical cancer, thyroid cancer, and ovarian cancer. (27)(28)(29)(30) Cheng et al (26) showed that the downregulation of YAP1 by verteporfin (a YAP1 inhibitor) sensitized cells to DNA-damaging agents.…”

Metformin mediates resensitivity to 5-fluorouracil in hepatocellular carcinoma via the suppression of YAP

“…Phosphorylation of YAP deactivated YAP and translocated it from the nucleus to the cytoplasm, which abolished its transcriptional activity. Overexpression of YAP is associated with chemoresistance in esophageal cancer, and its interaction with the TEAD binding site in the EGFR promoter resulted in increased EGFR expression at the transcriptional level, causing resistance to 5-Fu and docetaxel [32]. Dephosphorylation of YAP at Ser 127 dissociated it from 14-3-3 binding, leading to its nuclear assembly and transcriptional activation [33].…”