TNF receptor-associated factor 6 (TRAF6), a regulator of NF-κB signaling, has been reported to be associated with the oncogenesis of various tumors including pancreatic cancer, but the underlying mechanisms remain unknown. Here, we found that knocking down the expression of TRAF6 impaired YAP signaling. Moreover, TRAF6 promoted the migration and colony formation of pancreatic cancer cells through YAP. Then, we found that TRAF6 interacted with and promoted the ubiquitination and degradation of MST1, and the expression of TRAF6 and MST1 was negatively correlated in primary human pancreatic cancer samples. Our results reveal that TRAF6 regulates YAP signaling by promoting the ubiquitination and degradation of MST1 in pancreatic cancer, suggesting that TRAF6 could be a possible E3 ligase of MST1 and a potential therapeutic target.
Pancreatic cancer Tumorigenicity Ubiquitination TRAF6 MST1 Hippo–YAP NF-κB
This is a preview of subscription content, log in to check access.
This work was sponsored by the National Natural Science Foundation of China (Grant No. 81401923) and the Program of Shanghai Subject Chief Scientist (Grant No. 17XD1401200).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
Baud V, Liu Z-G, Bennett B, Suzuki N, Xia Y, Karin M. Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Dev. 1999;13:1297–308.CrossRefGoogle Scholar
Yin Q, Lin S-C, Lamothe B, et al. E2 interaction and dimerization in the crystal structure of TRAF6. Nat Struct Mol Biol. 2009;16:658–66.CrossRefGoogle Scholar
Deng L, Wang C, Spencer E, et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell. 2000;103:351–61.CrossRefGoogle Scholar
Yang W-L, Wang J, Chan C-H, et al. The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science. 2009;325:1134–8.CrossRefGoogle Scholar
Shi C-S, Kehrl JH. TRAF6 and A20 regulate lysine 63-linked ubiquitination of Beclin-1 to control TLR4-induced autophagy. Sci Signal. 2010;3:ra42.Google Scholar
Fang J, Bolanos LC, Choi K, et al. Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia. Nat Immunol. 2017;18:236–45.CrossRefGoogle Scholar
Starczynowski DT, Lockwood WW, Deléhouzée S, et al. TRAF6 is an amplified oncogene bridging the RAS and NF-κB pathways in human lung cancer. J Clin Invest. 2011;121:4095–105.CrossRefGoogle Scholar
Meng Q, Zheng M, Liu H, et al. TRAF6 regulates proliferation, apoptosis, and invasion of osteosarcoma cell. Mol Cell Biochem. 2012;371:177–86.CrossRefGoogle Scholar
Yao F, Han Q, Zhong C, Zhao H. TRAF6 promoted the tumorigenicity of esophageal squamous cell carcinoma. Tumour Biol. 2013;34:3201–7.CrossRefGoogle Scholar
Rong Y, Wang D, Wu W, et al. TRAF6 is over-expressed in pancreatic cancer and promotes the tumorigenicity of pancreatic cancer cells. Med Oncol. 2014;31:260.CrossRefGoogle Scholar
Zhao B, Li L, Lei Q, Guan K-L. The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev. 2010;24:862–74.CrossRefGoogle Scholar
Zhao B, Tumaneng K, Guan K-L. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat Cell Biol. 2011;13:877–83.CrossRefGoogle Scholar
Gumbiner BM, Kim N-G. The Hippo-YAP signaling pathway and contact inhibition of growth. J Cell Sci. 2014;127:709–17.CrossRefGoogle Scholar
Hong W, Guan K-L. The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway. Semin Cell Dev Biol. 2012;23:785–93.CrossRefGoogle Scholar
Dong J, Feldmann G, Huang J, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130:1120–33.CrossRefGoogle Scholar
Oudhoff MJ, Freeman SA, Couzens AL, et al. Control of the hippo pathway by Set7-dependent methylation of yap. Dev Cell. 2013;26:188–94.CrossRefGoogle Scholar
Lv H, Dong W, Cao Z, et al. TRAF6 is a novel NS3-interacting protein that inhibits classical swine fever virus replication. Sci Rep. 2017;7:6737.CrossRefGoogle Scholar
Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98–102.CrossRefGoogle Scholar
Mccain J. The cancer genome atlas: new weapon in old war? Biotechnol Healthc. 2006;3(2):46–51.Google Scholar
Lonsdale J, Thomas J, Salvatore M, et al. The genotype-tissue expression (GTEx) project. Nat Genet. 2013;13(5):307–8.Google Scholar
Qin F, Jing T, Zhou D, Chen L. Mst1 and Mst2 kinases: regulations and diseases. Cell Biosci. 2013;3:31.CrossRefGoogle Scholar
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.CrossRefGoogle Scholar
Song H, Mak KK, Topol L, et al. Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Natl Acad Sci. 2010;107:1431–6.CrossRefGoogle Scholar
Glantschnig H, Rodan GA, Reszka AA. Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylation. J Biol Chem. 2002;277:42987–96.CrossRefGoogle Scholar
Zhou D, Conrad C, Xia F, et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress the development of hepatocellular carcinoma through inactivation of the Yap1 oncogene. Cancer Cell. 2009;16:425–38.CrossRefGoogle Scholar
Bassères D, Baldwin A. Nuclear factor-kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression. Oncogene. 2006;25:6817–30.CrossRefGoogle Scholar
Lv Y, Kim K, Sheng Y, et al. YAP controls endothelial activation and vascular inflammation through TRAF6. Circ Res. 2018;123:43.CrossRefGoogle Scholar