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 Zhang; Michael Karin

doi:10.1073/pnas.1620290114

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 (Co-author)
, Kang Zhang

Michael Karin

German Cancer Consortium (DKTK)
Sun Yat-sen University Cancer Center
Medical University of Graz
University of Michigan Medical School
Medical University of Vienna

Research output: Contribution to journal › Original Article › peer-review

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 language	English
Pages (from-to)	1643-1648
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	7
DOIs	https://doi.org/10.1073/pnas.1620290114
Publication status	Published - 14 Feb 2017

Keywords

Adenomatous Polyposis Coli Protein/genetics
Adult
Aged
Animals
Carcinogenesis/genetics
Cell Cycle Proteins
Cell Line, Tumor
Colorectal Neoplasms/genetics
Cytokine Receptor gp130/genetics
Female
HCT116 Cells
HEK293 Cells
HT29 Cells
Humans
Male
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Middle Aged
Mutation
Nuclear Proteins/metabolism
Transcription Factors/metabolism
beta Catenin/genetics

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10.1073/pnas.1620290114

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

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title = "YAP-IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis",

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.",

keywords = "Adenomatous Polyposis Coli Protein/genetics, Adult, Aged, Animals, Carcinogenesis/genetics, Cell Cycle Proteins, Cell Line, Tumor, Colorectal Neoplasms/genetics, Cytokine Receptor gp130/genetics, Female, HCT116 Cells, HEK293 Cells, HT29 Cells, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Middle Aged, Mutation, Nuclear Proteins/metabolism, Transcription Factors/metabolism, beta Catenin/genetics",

author = "Koji Taniguchi and Toshiro Moroishi and \{de Jong\}, \{Petrus R\} and Michal Krawczyk and Grebbin, \{Britta Moyo\} and Huiyan Luo and Rui-Hua Xu and Nicole Golob-Schwarzl and Caroline Schweiger and Kepeng Wang and \{Di Caro\}, Giuseppe and Ying Feng and Fearon, \{Eric R\} and Eyal Raz and Lukas Kenner and Farin, \{Henner F\} and Kun-Liang Guan and Johannes Haybaeck and Christian Datz and Kang Zhang and Michael Karin",

note = "Datz: Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, 5110 Oberndorf, Austria",

year = "2017",

month = feb,

day = "14",

doi = "10.1073/pnas.1620290114",

language = "English",

volume = "114",

pages = "1643--1648",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

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Taniguchi, K, Moroishi, T, de Jong, PR, Krawczyk, M, Grebbin, BM, Luo, H, Xu, R-H, Golob-Schwarzl, N, Schweiger, C, Wang, K, Di Caro, G, Feng, Y, Fearon, ER, Raz, E, Kenner, L, Farin, HF, Guan, K-L, Haybaeck, J, Datz, C, Zhang, K & 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, vol. 114, no. 7, pp. 1643-1648. https://doi.org/10.1073/pnas.1620290114

TY - JOUR

T1 - YAP-IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis

AU - Taniguchi, Koji

AU - Moroishi, Toshiro

AU - de Jong, Petrus R

AU - Krawczyk, Michal

AU - Grebbin, Britta Moyo

AU - Luo, Huiyan

AU - Xu, Rui-Hua

AU - Golob-Schwarzl, Nicole

AU - Schweiger, Caroline

AU - Wang, Kepeng

AU - Di Caro, Giuseppe

AU - Feng, Ying

AU - Fearon, Eric R

AU - Raz, Eyal

AU - Kenner, Lukas

AU - Farin, Henner F

AU - Guan, Kun-Liang

AU - Haybaeck, Johannes

AU - Datz, Christian

AU - Zhang, Kang

AU - Karin, Michael

N1 - Datz: Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private University of Salzburg, 5110 Oberndorf, Austria

PY - 2017/2/14

Y1 - 2017/2/14

N2 - 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.

AB - 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.

KW - Adenomatous Polyposis Coli Protein/genetics

KW - Adult

KW - Aged

KW - Animals

KW - Carcinogenesis/genetics

KW - Cell Cycle Proteins

KW - Cell Line, Tumor

KW - Colorectal Neoplasms/genetics

KW - Cytokine Receptor gp130/genetics

KW - Female

KW - HCT116 Cells

KW - HEK293 Cells

KW - HT29 Cells

KW - Humans

KW - Male

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Middle Aged

KW - Mutation

KW - Nuclear Proteins/metabolism

KW - Transcription Factors/metabolism

KW - beta Catenin/genetics

U2 - 10.1073/pnas.1620290114

DO - 10.1073/pnas.1620290114

M3 - Original Article

C2 - 28130546

SN - 0027-8424

VL - 114

SP - 1643

EP - 1648

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 7

ER -

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

Abstract

Keywords

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