NF-kappaB-induced KIAA1199 promotes survival through EGFR signalling.

[en] Constitutive activation of EGFR- and NF-kappaB-dependent pathways is a hallmark of cancer, yet signalling proteins that connect both oncogenic cascades are poorly characterized. Here we define KIAA1199 as a BCL-3- and p65-dependent gene in transformed keratinocytes. KIAA1199 expression is enhanced on human papillomavirus (HPV) infection and is aberrantly expressed in clinical cases of cervical (pre)neoplastic lesions. Mechanistically, KIAA1199 binds Plexin A2 and protects from Semaphorin 3A-mediated cell death by promoting EGFR stability and signalling. Moreover, KIAA1199 is an EGFR-binding protein and KIAA1199 deficiency impairs EGF-dependent Src, MEK1 and ERK1/2 phosphorylations. Therefore, EGFR stability and signalling to downstream kinases requires KIAA1199. As such, KIAA1199 promotes EGF-mediated epithelial-mesenchymal transition (EMT). Taken together, our data define KIAA1199 as an oncogenic protein induced by HPV infection and constitutive NF-kappaB activity that transmits pro-survival and invasive signals through EGFR signalling.

Research center :

Giga-Signal Transduction - ULiège

Disciplines :

Oncology

Author, co-author :

Shostak, Kateryna ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale

Zhang, Xin

Hubert, Pascale ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques

Göktuna, Serkan ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale

Jiang, Zheshen

Klevernic, Iva ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale

Hildebrand, Julien

Roncarati, Patrick ; Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques

Hennuy, Benoît ; Université de Liège - ULiège > GIGA-Research

Ladang, Aurélie ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale

More authors (5 more)

Language :

English

Title :

NF-kappaB-induced KIAA1199 promotes survival through EGFR signalling.

Publication date :

2014

Journal title :

Nature Communications

eISSN :

2041-1723

Publisher :

Nature Publishing Group, United Kingdom

Volume :

Pages :

5232

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

WELBIO - Walloon Excellence in Life Sciences and Biotechnology [BE]
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Télévie [BE]
Fondation contre le Cancer [BE]
ULg FSR - Université de Liège. Fonds spéciaux pour la recherche [BE]

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Bibliography

Ghosh, S. & Hayden, M. S. New regulators of NF-kappaB in inflammation. Nat. Rev. Immunol. 8, 837-848 (2008).
Perkins, N. D. The diverse and complex roles of NF-kappaB subunits in cancer. Nat. Rev. Cancer 12, 121-132 (2012).
Budunova, I. V. et al. Increased expression of p50-NF-kappa B and constitutive activation of NF-kappa B transcription factors during mouse skin carcinogenesis. Oncogene 18, 7423-7431 (1999).
Van Waes, C. et al. Expression of a dominant-negative mutant inhibitor-kappa B alpha of nuclear factor-kappa B in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo. Cancer Res. 59, 3468-3474 (1999).
Van Waes, C. et al. Nuclear factor-kappa B is an important modulator of the altered gene expression profile and malignant phenotype in squamous cell carcinoma. Cancer Res. 64, 6511-6523 (2004).
Khavari, P. A., Seitz, C. S., Lin, Q. & Deng, H. Alterations in NF-kappa B function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-kappa B. Proc. Natl Acad. Sci. USA 95, 2307-2312 (1998).
Branca, M. et al. Upregulation of nuclear factor-kappaB (NF-kappaB) is related to the grade of cervical intraepithelial neoplasia, but is not an independent predictor of high-risk human papillomavirus or disease outcome in cervical cancer. Diagn. Cytopathol. 34, 555-563 (2006).
Nair, A., Venkatraman, M., Maliekal, T. T., Nair, B. & Karunagaran, D. NF-kappaB is constitutively activated in high-grade squamous intraepithelial lesions and squamous cell carcinomas of the human uterine cervix. Oncogene 22, 50-58 (2003).
Prusty, B. K., Husain, S. A. & Das, B. C. Constitutive activation of nuclear factor-kB: preferntial homodimerization of p50 subunits in cervical carcinoma. Front. Biosci. 10, 1510-1519 (2005).
Li, J. et al. Association of constitutive nuclear factor-kappaB activation with aggressive aspects and poor prognosis in cervical cancer. Int. J. Gynecol. Cancer 19, 1421-1426 (2009).
Richart, R. M. Causes and management of cervical intraepithelial neoplasia. Cancer 60(8 Suppl): 1951-1959 (1987).
zur Hausen, H. Papillomavirus infections-a major cause of human cancers. Biochim. Biophys. Acta 1288, F55-F78 (1996).
Hussain, I. et al. NF-kappaB protects human papillomavirus type 38 E6/E7-immortalized human keratinocytes against tumor necrosis factor alpha and UV-mediated apoptosis. J. Virol. 85, 9013-9022 (2011).
James, M. A., Lee, J. H. & Klingelhutz, A. J. Human papillomavirus type 16 E6 activates NF-kappaB, induces cIAP-2 expression, and protects against apoptosis in a PDZ binding motif-dependent manner. J. Virol. 80, 5301-5307 (2006).
Nees, M. et al. Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NFkappaB-responsive genes in cervical keratinocytes. J. Virol. 75, 4283-4296 (2001).
Havard, L., Delvenne, P., Frare, P., Boniver, J. & Giannini, S. L. Differential production of cytokines and activation of NF-kappaB in HPV-transformed keratinocytes. Virology 298, 271-285 (2002).
Havard, L., Rahmouni, S., Boniver, J. & Delvenne, P. High levels of p105 (NFKB1) and p100 (NFKB2) proteins in HPV16-transformed keratinocytes: role of E6 and E7 oncoproteins. Virology 331, 357-366 (2005).
Spitkovsky, D., Hehner, S. P., Hofmann, T. G., Moller, A. & Schmitz, M. L. The human papillomavirus oncoprotein E7 attenuates NF-kappa B activation by targeting the Ikappa B kinase complex. J. Biol. Chem. 277, 25576-25582 (2002).
McKeithan, T. W., Rowley, J. D., Shows, T. B. & Diaz, M. O. Cloning of the chromosome translocation breakpoint junction of the t(14;19) in chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 84, 9257-9260 (1987).
Viatour, P. et al. GSK3-mediated BCL-3 phosphorylation modulates its degradation and its oncogenicity. Mol. Cell 16, 35-45 (2004).
Mathas, S. et al. Elevated NF-kappaB p50 complex formation and Bcl-3 expression in classical Hodgkin, anaplastic large-cell, and other peripheral T-cell lymphomas. Blood 106, 4287-4293 (2005).
Brenne, A. T. et al. High expression of BCL3 in human myeloma cells is associated with increased proliferation and inferior prognosis. Eur. J. Haematol. 82, 354-363 (2009).
Canoz, O., Rassidakis, G. Z., Admirand, J. H. & Medeiros, L. J. Immunohistochemical detection of BCL-3 in lymphoid neoplasms: a survey of 353 cases. Mod. Pathol. 17, 911-917 (2004).
Nishikori, M. et al. High-level expression of BCL3 differentiates t(2;5)(p23;q35)-positive anaplastic large cell lymphoma from Hodgkin disease. Blood 101, 2789-2796 (2003).
Kashatus, D., Cogswell, P. & Baldwin, A. S. Expression of the Bcl-3 protooncogene suppresses p53 activation. Genes Dev. 20, 225-235 (2006).
Cogswell, P. C., Guttridge, D. C., Funkhouser, W. K. & Baldwin, Jr. A. S. Selective activation of NF-kappa B subunits in human breast cancer: potential roles for NF-kappa B2/p52 and for Bcl-3. Oncogene 19, 1123-1131 (2000).
O'Neil, B. H. et al. Expression of nuclear factor-kappaB family proteins in hepatocellular carcinomas. Oncology 72, 97-104 (2007).
Thornburg, N. J., Pathmanathan, R. & Raab-Traub, N. Activation of nuclear factor-kappaB p50 homodimer/Bcl-3 complexes in nasopharyngeal carcinoma. Cancer Res. 63, 8293-8301 (2003).
Ahlqvist, K., Saamarthy, K., Syed Khaja, A. S., Bjartell, A. & Massoumi, R. Expression of Id proteins is regulated by the Bcl-3 proto-oncogene in prostate cancer. Oncogene 32, 1601-1608 (2013).
Massoumi, R., Chmielarska, K., Hennecke, K., Pfeifer, A. & Fassler, R. Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Cell 125, 665-677 (2006).
Bignell, G. R. et al. Identification of the familial cylindromatosis tumoursuppressor gene. Nat. Genet. 25, 160-165 (2000).
Evensen, N. A. et al. Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration. J. Natl Cancer Inst. 105, 1402-1416 (2013).
Tiwari, A. et al. Early insights into the function of KIAA1199, a markedly overexpressed protein in human colorectal tumors. PLoS ONE 8, e69473 (2013).
Birkenkamp-Demtroder, K. et al. Repression of KIAA1199 attenuates Wntsignalling and decreases the proliferation of colon cancer cells. Br. J. Cancer 105, 552-561 (2011).
Sabates-Bellver, J. et al. Transcriptome profile of human colorectal adenomas. Mol. Cancer Res. 5, 1263-1275 (2007).
Matsuzaki, S. et al. Clinicopathologic significance of KIAA1199 overexpression in human gastric cancer. Ann. Surg. Oncol. 16, 2042-2051 (2009).
Yoshida, H. et al. KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization. Proc. Natl Acad. Sci. USA 110, 5612-5617 (2013).
Michishita, E., Garces, G., Barrett, J. C. & Horikawa, I. Upregulation of the KIAA1199 gene is associated with cellular mortality. Cancer Lett. 239, 71-77 (2006).
Dicker, A. P. et al. Malignant transformation of immortalized HaCaT keratinocytes through deregulated nuclear factor kappa B signaling. Cancer Res. 66, 5209-5215 (2006).
Keutgens, A. et al. BCL-3 degradation involves its polyubiquitination through a FBW7-independent pathway and its binding to the proteasome subunit PSMB1. J. Biol. Chem. 285, 25831-25840 (2010).
An, J. et al. Inactivation of the CYLD deubiquitinase by HPV E6 mediates hypoxia-induced NF-kappa B activation. Cancer Cell 14, 394-407 (2008).
Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J. & Howley, P. M. The E6 oncoprotein encoded by human papillomavirus type-16 and type-18 promotes the degradation of P53. Cell 63, 1129-1136 (1990).
Nakayama, M., Kikuno, R. & Ohara, O. Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs. Genome Res. 12, 1773-1784 (2002).
He, Q. Y. et al. G8: a novel domain associated with polycystic kidney disease and non-syndromic hearing loss. Bioinformatics 22, 2189-2191 (2006).
Neufeld, G. & Kessler, O. The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nat. Rev. Cancer 8, 632-645 (2008).
Castro-Rivera, E., Ran, S., Brekken, R. A. & Minna, J. D. Semaphorin 3B inhibits the phosphatidylinositol 3-kinase/Akt pathway through neuropilin-1 in lung and breast cancer cells. Cancer Res. 68, 8295-8303 (2008).
Tamagnone, L. Emerging role of semaphorins as major regulatory signals and potential therapeutic targets in cancer. Cancer Cell 22, 145-152 (2012).
Casazza, A. et al. Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice. J. Clin. Invest. 120, 2684-2698 (2010).
Yamaoka, T. et al. Transactivation of EGF receptor and ErbB2 protects intestinal epithelial cells from TNF-induced apoptosis. Proc. Natl Acad. Sci. USA 105, 11772-11777 (2008).
Lee, M. Y., Chou, C. Y., Tang, M. J. & Shen, M. R. Epithelial-mesenchymal transition in cervical cancer: correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulation. Clin. Cancer Res. 14, 4743-4750 (2008).
Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704-715 (2008).
Kuscu, C. et al. Transcriptional and epigenetic regulation of KIAA1199 gene expression in human breast cancer. PLoS ONE 7, e44661 (2012).
Yamaoka, S. et al. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell 93, 1231-1240 (1998).
Rothwarf, D. M., Zandi, E., Natoli, G. & Karin, M. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature 395, 297-300 (1998).
Huber, M. A. et al. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J. Clin. Invest. 114, 569-581 (2004).
Massoumi, R. et al. Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma. J. Exp. Med. 206, 221-232 (2009).
Wilding, J. et al. E-cadherin transfection down-regulates the epidermal growth factor receptor and reverses the invasive phenotype of human papilloma virustransfected keratinocytes. Cancer Res. 56, 5285-5292 (1996).
Caberg, J. H. et al. Silencing of E7 oncogene restores functional E-cadherin expression in human papillomavirus 16-transformed keratinocytes. Carcinogenesis 29, 1441-1447 (2008).
Spangle, J. M. & Munger, K. The HPV16 E6 oncoprotein causes prolonged receptor protein tyrosine kinase signaling and enhances internalization of phosphorylated receptor species. PLoS Pathog. 9, e1003237 (2013).
Chivu Economescu, M. et al. Identification of potential biomarkers for early and advanced gastric adenocarcinoma detection. Hepatogastroenterology 57, 1453-1464 (2010).
Keutgens, A. et al. The repressing function of the oncoprotein BCL-3 requires CtBP, while its polyubiquitination and degradation involve the E3 ligase TBLR1. Mol. Cell. Biol. 30, 4006-4021 (2010).
Delvenne, P., Fontaine, M. A., Delvenne, C., Nikkels, A. & Boniver, J. Detection of human papillomaviruses in paraffin-embedded biopsies of cervical intraepithelial lesions-analysis by immunohistochemistry, in-situ hybridization, and the polymerase chain-reaction. Mod. Pathol. 7, 113-119 (1994).
Qu, W. M. et al. PCR detection of human papillomavirus: comparison between MY09/MY11 and GP5+/GP6+ primer systems. J. Clin. Microbiol. 35, 1304-1310 (1997).
Jacobs, M. V. et al. A general primer GP5+/GP6+-mediated PCR-enzyme immunoassay method for rapid detection of 14 high-risk and 6 low-risk human papillomavirus genotypes in cervical scrapings. J. Clin. Microbiol. 35, 791-795 (1997).
Mori, S. et al. Biased amplification of human papillomavirus DNA in specimens containing multiple human papillomavirus types by PCR with consensus primers. Cancer Sci. 102, 1223-1227 (2011).
Park, H. S. et al. Application of physical force is essential to enrich for epidermal stem cells in primary human keratinocyte isolation. Tissue Eng. 10, 343-351 (2004).
Hubert, P. et al. E-cadherin-dependent adhesion of dendritic and Langerhans cells to keratinocytes is defective in cervical human papillomavirus-associated (pre)neoplastic lesions. J. Pathol. 206, 346-355 (2005).
Hanafusa, H. et al. Leucine-rich repeat kinase LRRK1 regulates endosomal trafficking of the EGF receptor. Nat. Commun. 2, 158 (2011).
Sorkin, A. & Carpenter, G. Dimerization of internalized epidermal growth factor receptors. J. Biol. Chem. 266, 23453-23460 (1991).
Lopez, J., Poitevin, A., Mendoza-Martinez, V., Perez-Plasencia, C. & Garcia-Carranca, A. Cancer-initiating cells derived from established cervical cell lines exhibit stem-cell markers and increased radioresistance. BMC Cancer 12, 48 (2012).