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 - Funding Information:
We thank Drs. D. Pan (Johns Hopkins University) and S. Akira (Osaka University) for YapF/F and Stat3F/F mice, respectively; Drs. D. L. Gumucio (University of Michigan) for the 12.4-kb Villin promoter; C. A. O'Brien (University of Arkansas for Medical Sciences) for the gp130-luciferase plasmid; T. Sato (Keio University), H. Clevers (Hubrecht Institute), and Y. Hippo (National Cancer Center Research Institute) for protocols describing intestinal organoid culture; C. Kuo (Stanford University) for R-spondin1-producing cells; J. Zhao [University of California, San Diego (UCSD) Transgenic Mouse and Gene Targeting Core], L. Gapuz, R. Ly, and N. Varki (UCSD Histology Core), N. Hiramatsu, S. Yamachika, S. I. Grivennikov, A. Chang, and T. Lee for technical advice and assistance; and Cell Signaling, Santa Cruz Biotechnology, GeneTex, and Incyte for antibodies and reagents. This work was supported by Postdoctoral Fellowship for Research Abroad and Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science, a Uehara Memorial Foundation Fellowship, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Kanae Foundation for the Promotion of Medical Science, KAKENHI (15K21775), and the "Kibou" Projects (all to K.T.); FIRC for Abroad and iCare fellowship funded from the Italian Association for Cancer Research and Marie Curie Actions European Union-People-COFUND (G.D.C.); and Crohn's and Colitis Foundation of America SRA#330251 (to E.R.). L.K. is supported by the European Commission Marie Curie 2020 program as a Co-Coordinator within the "ALKATRAS' project as well as by the Austrian Science Funds FWF; and Grants P26011 and P29251. TMA generation was supported by the Innovative Medicines Initiative Joint Undertaking under Grant 115234 (OncoTrack), resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations companies' in-kind contribution (www.imi.europa.eu) (to J.H.). C.D. was supported by SPAR Austria. Research at UCSD was supported by the NIH (AI043477) and Incyte Inc. M. Karin is an American Cancer Society Research Professor and holder of the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.
Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.
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
KW - Colorectal cancer
KW - IL-6ST/gp130
KW - STAT3
KW - YAP
UR - http://www.scopus.com/inward/record.url?scp=85013040105&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85013040105&partnerID=8YFLogxK
U2 - 10.1073/pnas.1620290114
DO - 10.1073/pnas.1620290114
M3 - Article
C2 - 28130546
AN - SCOPUS:85013040105
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 -
