YAP-IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis

Koji Taniguchi, Toshiro Moroishi, Petrus R. De Jong, Michal Krawczyk, Britta Moyo Grebbin, Huiyan Luo, Rui Hua Xu, Nicole Golob-Schwarzl, Caroline Schweiger, Kepeng Wang, Giuseppe Di Caro, Ying Feng, Eric R. Fearon, Eyal Raz, Lukas Kenner, Henner F. Farin, Kun Liang Guan, Johannes Haybaeck, Christian Datz, Kang ZhangMichael Karin

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32 Citations (Scopus)

Abstract

Loss of tumor suppressor adenomatous polyposis coli (APC) activates β-catenin to initiate colorectal tumorigenesis. However, β-catenin (CTNNB1) activating mutations rarely occur in human colorectal cancer (CRC). We found that APC loss also results in up-regulation of IL-6 signal transducer (IL-6ST/gp130), thereby activating Src family kinases (SFKs), YAP, and STAT3, which are simultaneously up-regulated in the majority of human CRC. Although, initial YAP activation, which stimulates IL6ST gene transcription, may be caused by reduced serine phosphorylation, sustained YAP activation depends on tyrosine phosphorylation by SFKs, whose inhibition, along with STAT3-activating JAK kinases, causes regression of established colorectal tumors. These results explain why APC loss is a more potent initiating event than the mere activation of CTNNB1.

Original languageEnglish
Pages (from-to)1643-1648
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number7
DOIs
Publication statusPublished - 2017 Feb 14

Keywords

  • Adenomatous polyposis coli
  • Colorectal cancer
  • IL-6ST/gp130
  • STAT3
  • YAP

ASJC Scopus subject areas

  • General

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  • Cite this

    Taniguchi, K., Moroishi, T., De Jong, P. R., Krawczyk, M., Grebbin, B. M., Luo, H., Xu, R. H., Golob-Schwarzl, N., Schweiger, C., Wang, K., Di Caro, G., Feng, Y., Fearon, E. R., Raz, E., Kenner, L., Farin, H. F., Guan, K. L., Haybaeck, J., Datz, C., ... Karin, M. (2017). YAP-IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America, 114(7), 1643-1648. https://doi.org/10.1073/pnas.1620290114