A06: Role of atypical IκB protein IκBζ in HCC formation

Although NFκB has intensively been investigated for its role in inflammation and tumorigenesis, the identification a novel subfamily of so-called atypical IκB proteins has added a fascinating new control layer to the complex biology of this transcription factor. The four atypical members – IκBζ, IκBNS, IκBη and Bcl-3 – differ considerably from classical IκB proteins that typically inhibit gene expression by sequestering NFκB in the cytoplasm. In contrast, atypical IκBs are exclusively localized in the nucleus where they can repress but, more importantly, also activate selected target genes largely by chromatin remodeling events. We have recently elucidated an essential role of IκBζ and IκBNS in macrophage and T cell polarization. Importantly, we found that IκBζ-deficient mice are completely resistant to the development of highly aggressive liver tumors triggered by transposon-based overexpression of oncogenic c-Myc, Nras and p53 knockdown. In addition, we discovered that IκBζ is indispensable for the expression of key cytokines, such as IL-6, IL-10 and CCL2, which impair immunosurveillance or promote HCC progression. Intriguingly, also metabolic reprogramming seems to be controlled by IκBζ, suggesting that multiple liver-intrinsic and immune-mediated mechanisms contribute to the tumor-promoting function of IκBζ. The aim of this project is to investigate the role of atypical IκBs, in particular IκBζ, for the development of mouse and human liver tumors. Through interaction within the CRC we will explore the role of IκBζ not only in transposon- based HCC, but also in inflammation- and metabolic syndrome-driven cancer models. By employing cell type-specific knockout mice we will dissect the specific oncogenic function of IκBζ in hepatocytes and immune cells. Moreover, we will define specific target genes involved in the regulation of cell survival, metabolism and immune response that contribute to HCC development. Collectively, this project will provide not only new insights into the oncogenic role of atypical IκBs, but as a long-term goal might also provide new therapeutic opportunities to interfere with selective NFκB responses in disease processes.

Publications

Hörber S, Hildebrand DG, Lieb WS, Lorscheid S, Hailfinger S, Schulze-Osthoff K*, Essmann F* (2016) The Atypical Inhibitor of NF-κB, IκBζ, Controls Macrophage Interleukin-10 Expression. J Biol Chem 291:12851-61 (*equal senior authorship).
Schmitt A, Grondona P, Maier T, Brändle M, Schönfeld C, Jäger G, Kosnopfel C, Eberle FC, Schittek B, Schulze-Osthoff K, Yazdi AS, Hailfinger S (2016) MALT1 Protease Activity Controls the Expression of Inflammatory Genes in Keratinocytes upon Zymosan Stimulation. J Invest Dermatol 136:788- 97.
Johansen C, Mose M, Ommen P, Bertelsen T, Vinter H, Hailfinger S, Lorscheid S, Schulze-Osthoff K, Iversen L (2015) IκBζ is a key driver in the development of psoriasis. Proc Natl Acad Sci U S A 112:E5825-33.
Braumüller H, Wieder T, Brenner E, Aßmann S, Hahn M, Alkhaled M, Schilbach K, Essmann F, Kneilling M, Griessinger C, Ranta F, Ullrich S, Mocikat R, Braungart K, Mehra T, Berdel J, Niessner H, Meier F, van den Broek M, Häring HU, Handgretinger R, Quintanilla-Martinez L, Fend F, Pesic M, Bauer J, Zender L, Schaller M, Schulze-Osthoff K, Röcken M (2013) T-helper-1-cell cytokines drive cancer into senescence. Nature 494:361-5.
Hildebrand DG, Alexander E, Hörber S, Lehle S, Obermayer K, Münck NA, Rothfuss O, Frick JS, Morimatsu M, Schmitz I, Roth J, Ehrchen JM, Essmann F, Schulze-Osthoff K (2013) IκBζ is a transcriptional key regulator of CCL2/MCP-1. J Immunol 190:4812-20.
Nogai H, Wenzel SS, Hailfinger S, Grau M, Kaergel E, Seitz V, Wollert-Wulf B, Pfeifer M, Wolf A, Frick M, Dietze K, Madle H, Tzankov A, Hummel M, Dörken B, Scheidereit C, Janz M, Lenz P, Thome M, Lenz G (2013) IκBζ controls the constitutive NF-κB target gene network and survival of ABC DLBCL. Blood 122:2242-50.
Schuster M, Glauben R, Plaza-Sirvent C, Schreiber L, Annemann M, Kühl AA, Clayton LK, Sparwasser T, Schulze-Osthoff K, Pfeffer K, Huehn J, Siegmund B, Schmitz I (2012) IκB(NS) protein mediates regulatory T cell development via induction of the Foxp3 transcription factor. Immunity 37:998-1008.
Hailfinger S, Nogai H, Pelzer C, Jaworski M, Cabalzar K, Charton JE, Guzzardi M, Décaillet C, Grau M, Dörken B, Lenz P, Lenz G, Thome M (2011) Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines. Proc Natl Acad Sci U S A 108:14596- 601.