EIF5A-PEAK1 signaling regulates YAP1/TAZ protein expression and pancreatic cancer cell growth

Jan Strnadel, Sunkyu Choi, Ken Fujimura, Huawei Wang, Wei Zhang, Meghan Wyse, Tracy Wright, Emilie Gross, Carlos Peinado, Hyun Woo Park, Jack Bui, Jonathan Kelber, Michael Bouvet, Kun Liang Guan, Richard L. Klemke

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31 Citations (Scopus)

Abstract

In pancreatic ductal adenocarcinoma (PDAC), mutant KRAS stimulates the translation initiation factor eIF5A and upregulates the focal adhesion kinase PEAK1, which transmits integrin and growth factor signals mediated by the tumor microenvironment. Although eIF5A-PEAK1 signaling contributes to multiple aggressive cancer cell phenotypes, the downstream signaling processes that mediate these responses are uncharacterized. Through proteomics and informatic analyses of PEAK1-depleted PDAC cells, we defined protein translation, cytoskeleton organization, and cell-cycle regulatory pathways as major pathways controlled by PEAK1. Biochemical and functional studies revealed that the transcription factors YAP1 and TAZ are key targets of eIF5APEAK1 signaling. YAP1/TAZ coimmunoprecipitated with PEAK1. Interfering with eIF5A-PEAK1 signaling in PDAC cells inhibited YAP/TAZ protein expression, decreasing expression of stem cell- associated transcription factors (STF) including Oct4, Nanog, c- Myc, and TEAD, thereby decreasing three-dimensional (3D) tumor sphere growth. Conversely, amplified eIF5A-PEAK1 signaling increased YAP1/TAZ expression, increasing expression of STF and enhancing 3D tumor sphere growth. Informatic interrogation of mRNA sequence databases revealed upregulation of the eIF5A-PEAK1-YAP1-TEAD signaling module in PDAC patients. Taken together, our findings indicate that eIF5APEAK1-YAP signaling contributes to PDAC development by regulating an STF program associated with increased tumorigenicity.

Original languageEnglish
Pages (from-to)1997-2007
Number of pages11
JournalCancer Research
Volume77
Issue number8
DOIs
Publication statusPublished - 2017 Apr 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Strnadel, J., Choi, S., Fujimura, K., Wang, H., Zhang, W., Wyse, M., Wright, T., Gross, E., Peinado, C., Park, H. W., Bui, J., Kelber, J., Bouvet, M., Guan, K. L., & Klemke, R. L. (2017). EIF5A-PEAK1 signaling regulates YAP1/TAZ protein expression and pancreatic cancer cell growth. Cancer Research, 77(8), 1997-2007. https://doi.org/10.1158/0008-5472.CAN-16-2594