The hippo coactivator YAP1 mediates EGFR overexpression and confers chemoresistance in esophageal cancer

Shumei Song, Soichiro Honjo, Jiankang Jin, Shih Shin Chang, Ailing W. Scott, Qiongrong Chen, Neda Kalhor, Arlene M. Correa, Wayne L. Hofstetter, Constance T. Albarracin, Tsung Teh Wu, Randy L. Johnson, Mien Chie Hung, Jaffer A. Ajani

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Abstract

Purpose: Esophageal cancer is an aggressive malignancy and often resistant to therapy. Overexpression of EGFR has been associated with poor prognosis of patients with esophageal cancer. However, clinical trials using EGFR inhibitors have not provided benefit for patients with esophageal cancer. Failure of EGFR inhibition may be due to crosstalk with other oncogenic pathways. Experimental Design: In this study, expression of YAP1 and EGFR were examined in EAC-resistant tumor tissues versus sensitive tissues by IHC. Western blot analysis, immunofluorescence, real-time PCR, promoter analysis, site-directed mutagenesis, and in vitro and in vivo functional assays were performed to elucidate the YAP1-mediated EGFR expression and transcription and the relationship with chemoresistance in esophageal cancer. Results: Wedemonstrate that Hippo pathway coactivator YAP1 can induce EGFR expression and transcription in multiple cell systems. Both YAP1 and EGFR are overexpressed in resistant esophageal cancer tissues compared with sensitive esophageal cancer tissues. Furthermore, we found that YAP1 increases EGFR expression at the level of transcription requiring an intact TEADbinding site in the EGFR promoter. Most importantly, exogenous induction of YAP1 induces resistance to 5-fluorouracil and docetaxcel, whereas knockdown of YAP1 sensitizes esophageal cancer cells to these cytotoxics. Verteporfin, a YAP1 inhibitor, effectively inhibits both YAP1 and EGFR expression and sensitizes cells to cytotoxics. Conclusions: Our data provide evidence that YAP1 upregulation of EGFR plays an important role in conferring therapy resistance in esophageal cancer cells. Targeting YAP1-EGFR axis may be more efficacious than targeting EGFR alone in esophageal cancer.

Original languageEnglish (US)
Pages (from-to)2580-2590
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number11
DOIs
StatePublished - Jun 1 2015

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Esophageal Neoplasms
Site-Directed Mutagenesis
Fluorouracil
Fluorescent Antibody Technique
Real-Time Polymerase Chain Reaction
Neoplasms
Research Design
Up-Regulation
Western Blotting
Clinical Trials
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Song, S., Honjo, S., Jin, J., Chang, S. S., Scott, A. W., Chen, Q., ... Ajani, J. A. (2015). The hippo coactivator YAP1 mediates EGFR overexpression and confers chemoresistance in esophageal cancer. Clinical Cancer Research, 21(11), 2580-2590. https://doi.org/10.1158/1078-0432.CCR-14-2191

The hippo coactivator YAP1 mediates EGFR overexpression and confers chemoresistance in esophageal cancer. / Song, Shumei; Honjo, Soichiro; Jin, Jiankang; Chang, Shih Shin; Scott, Ailing W.; Chen, Qiongrong; Kalhor, Neda; Correa, Arlene M.; Hofstetter, Wayne L.; Albarracin, Constance T.; Wu, Tsung Teh; Johnson, Randy L.; Hung, Mien Chie; Ajani, Jaffer A.

In: Clinical Cancer Research, Vol. 21, No. 11, 01.06.2015, p. 2580-2590.

Research output: Contribution to journalArticle

Song, S, Honjo, S, Jin, J, Chang, SS, Scott, AW, Chen, Q, Kalhor, N, Correa, AM, Hofstetter, WL, Albarracin, CT, Wu, TT, Johnson, RL, Hung, MC & Ajani, JA 2015, 'The hippo coactivator YAP1 mediates EGFR overexpression and confers chemoresistance in esophageal cancer', Clinical Cancer Research, vol. 21, no. 11, pp. 2580-2590. https://doi.org/10.1158/1078-0432.CCR-14-2191
Song, Shumei ; Honjo, Soichiro ; Jin, Jiankang ; Chang, Shih Shin ; Scott, Ailing W. ; Chen, Qiongrong ; Kalhor, Neda ; Correa, Arlene M. ; Hofstetter, Wayne L. ; Albarracin, Constance T. ; Wu, Tsung Teh ; Johnson, Randy L. ; Hung, Mien Chie ; Ajani, Jaffer A. / The hippo coactivator YAP1 mediates EGFR overexpression and confers chemoresistance in esophageal cancer. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 11. pp. 2580-2590.
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abstract = "Purpose: Esophageal cancer is an aggressive malignancy and often resistant to therapy. Overexpression of EGFR has been associated with poor prognosis of patients with esophageal cancer. However, clinical trials using EGFR inhibitors have not provided benefit for patients with esophageal cancer. Failure of EGFR inhibition may be due to crosstalk with other oncogenic pathways. Experimental Design: In this study, expression of YAP1 and EGFR were examined in EAC-resistant tumor tissues versus sensitive tissues by IHC. Western blot analysis, immunofluorescence, real-time PCR, promoter analysis, site-directed mutagenesis, and in vitro and in vivo functional assays were performed to elucidate the YAP1-mediated EGFR expression and transcription and the relationship with chemoresistance in esophageal cancer. Results: Wedemonstrate that Hippo pathway coactivator YAP1 can induce EGFR expression and transcription in multiple cell systems. Both YAP1 and EGFR are overexpressed in resistant esophageal cancer tissues compared with sensitive esophageal cancer tissues. Furthermore, we found that YAP1 increases EGFR expression at the level of transcription requiring an intact TEADbinding site in the EGFR promoter. Most importantly, exogenous induction of YAP1 induces resistance to 5-fluorouracil and docetaxcel, whereas knockdown of YAP1 sensitizes esophageal cancer cells to these cytotoxics. Verteporfin, a YAP1 inhibitor, effectively inhibits both YAP1 and EGFR expression and sensitizes cells to cytotoxics. Conclusions: Our data provide evidence that YAP1 upregulation of EGFR plays an important role in conferring therapy resistance in esophageal cancer cells. Targeting YAP1-EGFR axis may be more efficacious than targeting EGFR alone in esophageal cancer.",
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T1 - The hippo coactivator YAP1 mediates EGFR overexpression and confers chemoresistance in esophageal cancer

AU - Song, Shumei

AU - Honjo, Soichiro

AU - Jin, Jiankang

AU - Chang, Shih Shin

AU - Scott, Ailing W.

AU - Chen, Qiongrong

AU - Kalhor, Neda

AU - Correa, Arlene M.

AU - Hofstetter, Wayne L.

AU - Albarracin, Constance T.

AU - Wu, Tsung Teh

AU - Johnson, Randy L.

AU - Hung, Mien Chie

AU - Ajani, Jaffer A.

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Y1 - 2015/6/1

N2 - Purpose: Esophageal cancer is an aggressive malignancy and often resistant to therapy. Overexpression of EGFR has been associated with poor prognosis of patients with esophageal cancer. However, clinical trials using EGFR inhibitors have not provided benefit for patients with esophageal cancer. Failure of EGFR inhibition may be due to crosstalk with other oncogenic pathways. Experimental Design: In this study, expression of YAP1 and EGFR were examined in EAC-resistant tumor tissues versus sensitive tissues by IHC. Western blot analysis, immunofluorescence, real-time PCR, promoter analysis, site-directed mutagenesis, and in vitro and in vivo functional assays were performed to elucidate the YAP1-mediated EGFR expression and transcription and the relationship with chemoresistance in esophageal cancer. Results: Wedemonstrate that Hippo pathway coactivator YAP1 can induce EGFR expression and transcription in multiple cell systems. Both YAP1 and EGFR are overexpressed in resistant esophageal cancer tissues compared with sensitive esophageal cancer tissues. Furthermore, we found that YAP1 increases EGFR expression at the level of transcription requiring an intact TEADbinding site in the EGFR promoter. Most importantly, exogenous induction of YAP1 induces resistance to 5-fluorouracil and docetaxcel, whereas knockdown of YAP1 sensitizes esophageal cancer cells to these cytotoxics. Verteporfin, a YAP1 inhibitor, effectively inhibits both YAP1 and EGFR expression and sensitizes cells to cytotoxics. Conclusions: Our data provide evidence that YAP1 upregulation of EGFR plays an important role in conferring therapy resistance in esophageal cancer cells. Targeting YAP1-EGFR axis may be more efficacious than targeting EGFR alone in esophageal cancer.

AB - Purpose: Esophageal cancer is an aggressive malignancy and often resistant to therapy. Overexpression of EGFR has been associated with poor prognosis of patients with esophageal cancer. However, clinical trials using EGFR inhibitors have not provided benefit for patients with esophageal cancer. Failure of EGFR inhibition may be due to crosstalk with other oncogenic pathways. Experimental Design: In this study, expression of YAP1 and EGFR were examined in EAC-resistant tumor tissues versus sensitive tissues by IHC. Western blot analysis, immunofluorescence, real-time PCR, promoter analysis, site-directed mutagenesis, and in vitro and in vivo functional assays were performed to elucidate the YAP1-mediated EGFR expression and transcription and the relationship with chemoresistance in esophageal cancer. Results: Wedemonstrate that Hippo pathway coactivator YAP1 can induce EGFR expression and transcription in multiple cell systems. Both YAP1 and EGFR are overexpressed in resistant esophageal cancer tissues compared with sensitive esophageal cancer tissues. Furthermore, we found that YAP1 increases EGFR expression at the level of transcription requiring an intact TEADbinding site in the EGFR promoter. Most importantly, exogenous induction of YAP1 induces resistance to 5-fluorouracil and docetaxcel, whereas knockdown of YAP1 sensitizes esophageal cancer cells to these cytotoxics. Verteporfin, a YAP1 inhibitor, effectively inhibits both YAP1 and EGFR expression and sensitizes cells to cytotoxics. Conclusions: Our data provide evidence that YAP1 upregulation of EGFR plays an important role in conferring therapy resistance in esophageal cancer cells. Targeting YAP1-EGFR axis may be more efficacious than targeting EGFR alone in esophageal cancer.

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