A new protagonist in cell survival

What do solid tumours, certain congenital types of deafness and rheumatoid arthritis have in common? A deregulation in the function of the protein KIAA1199! In a study published in Nature communications, researchers from the University of Liège reveal the link between this protein and a receptor known as EGFR, a key protagonist in tumour development and progression. A link that could be of importance for these human diseases...

Familial cylindromatosis, also known as turban tumour syndrome, is a genetic disease that leads to the formation of large benign tumours, essentially on the head. They result from the hyperproliferation and the prolonged survival of keratinocytes, the predominant cell type in the epidermis. "One of the reasons why these people spontaneously develop these tumours is that they exhibit an overexpression of the protein Bcl-3 in their keratinocytes", explains Professor Alain Chariot, project leader at GIGA’s Laboratory of Medical Chemistry at the University of Liège.
 While studying this disease, Alain Chariot and his colleagues could not imagine where their research was going to bring them... They focus their work on the identification and characterization of proteins that promote tumor development and progression up to metastasis. “We dissect at the molecular level all protagonists that somehow play some role in the development and progression of cancer”, Alain Chariot specifies. “Once we have a precise idea on how these proteins intervene, we inactivate the corresponding genes in mice in order to address the consequences on tumor development”. For this purpose, the scientists combine a whole series of approaches: microarray (DNA chip), transgenesis, and molecular and cellular biology. In some cases, the inactivation of a gene manages to block or to delay tumour development and the researchers can subsequently record the protein in question as one main protagonist in tumour development.

A protein that activates some key survival pathways

Within the framework of its research on familial cylindromatosis, Alain Chariot’s team studied the cellular consequences of overexpressing Bcl-3. What happens in cells when this protein is expressed in large amounts? "We used the DNA chip approach to identify all gene candidates induced following the overexpression of Bcl-3 in immortalized keratinocytes. The most intensively induced candidate upon Bcl-3 overexpression was KIAA1199". Following these observations, the researchers made the link with another disease in which keratinocytes are proliferating too much:  cervical cancer. “This cancer results from an infection by the oncogenic human papillomavirus (HPV). When patients develop this type of cancer following HPV infection, they also exhibit large amounts of the Bcl-3 protein, which leads to the overexpression of its target gene KIAA1199", explains Alain Chariot, who established a fruitful collaboration with the team of Professor Philippe Delvenne at GIGA’s Laboratory of Experimental Pathology, ULg. But why does HPV induce this gene? It was still unclear at that time what the KIAA1199 protein was actually doing. The researchers from Liège provided some answers to this question in an article published in Nature Communications (1). “We show that this protein promotes cell survival in keratinocytes. If we deprive these cells from the protein KIAA1199, the keratinocytes die. The overexpression of this gene is therefore one of the reasons why patients develop cervical cancer, because HPV triggers the expression of this protein to sustain cell survival in the infected keratinocytes. As they survive longer, cancerous cells can accumulate and tumor growth occurs", Alain Chariot reveals.

A close link with a key player in tumour progress

Why do cells survive longer when the protein KIAA1199 is more expressed? Because it stabilizes a receptor well known to cancer specialists: EGFR (epidermal growth factor receptor). “When this receptor is stabilised, it is active and induces survival and cell invasion. On the other hand, when it is destabilised and no longer functional, cells die”, Alain Chariot points out. Furthermore, in parallel to the activation of this cell survival signalling pathway via EGFR, the protein KIAA1199 also limits some cell death pathways. “More specifically, it prevents semaphorin 3A from triggering a series of reactions leading to cell death”, the researcher specifies.

By establishing this link between the protein KIAA1199 and EGFR, scientists have pinpointed a key mechanism in the development of cervical cancers, a mechanism that is most likely relevant to many other types of cancers. “All solid tumours in which EGFR has a constitutive activity may also rely on KIAA1199 for their growth. In this case, cancers of the lung, pancreas or glioblastoma”, Alain Chariot emphasises. “In other types of cancer in which activating EGFR mutations are rarely found, it is other members of this family of receptors that are amplified. This is especially true for the HER-2 gene in 15 % of breast tumours. It is likely that they also need the protein KIAA1199 to induce cell survival and invasion signals". Hence, the identification of this “simple” connection between KIAA1199 and EGFR is relevant for a whole array of cancers and could therefore be an interesting avenue for the treatment of many people.

Overcoming the resistance of cancerous cells

Since research in molecular biology succeeded in defining EGFR as a key player for the development of numerous solid tumours, this receptor has become one of the therapeutic targets in the treatment of these tumours.

There are currently specific inhibitors for EGFR. They are administered to patients suffering from tumours exhibiting a high activity of this receptor. “Following the treatment, tumour regression is significant. But after a few weeks, the cancerous cell – which has a high level of plasticity – can establish a genetic program to escape from cell death triggered by the chemotherapy and this is certainly true for EGFR inhibitors”, Alain Chariot explains. “Cancer cells find other means to activate parallel pathways to circumvent the blockage of EGFR activity.” This strategy allows cancerous cells to become resistant, thus leading to a relapse. “We are beginning to identify these parallel pathways”, the scientist continues. “We now know at least three brothers and sisters of EGFR that can be hyperactivated in cancerous cells in which EGFR activity is blocked”. We can therefore understand the interest of targeting KIAA1199. Indeed, by preventing this protein’s action, not only will this lead to the destabilisation – and hence, inhibition – of EGFR, but also that of other members of its family. Therefore, none of these receptors will send survival and invasion signals to cancerous cells anymore. “We believe that it’s worth trying to find a way to inhibit the protein KIAA1199 to overcome resistance to treatment against EGFR”, the specialist emphasises.

A gene, a protein, three diseases concerned

Besides its role in tumour progression, the protein KIAA1199 may also be linked to other human diseases when not properly expressed: certain types of congenital deafness and chronic inflammatory diseases such as rheumatoid arthritis. “In the first case, the protein doesn’t correctly function and in the second case, it is overexpressed”, Alain Chariot points out. “Our work is therefore likely to gain interest from research teams who study mechanisms underlying cancerous and inflammatory diseases, and lesions of the inner ear". Beginning with fundamental research on a genetic disease, the scientist and his colleagues progressed step by step, guided by their intuition and their observations, and revealed a molecular player and the consequences of its deregulation in seemingly very distinct diseases. Carried out mainly thanks to the support of WELBIO, the FNRS, Télévie, the Belgian Federation against Cancer and the Anti-Cancer Centre, this work is still in progress and now includes the collaboration of a couple of additional ULg’s laboratories. “We have launched a collaboration with the teams of Professor Brigitte Malgrange of GIGA-Neurosciences and Professor Michel Malaise from the Rheumatology Department at Liège’s CHU”, Alain Chariot continues. “We shall continue to work on the role of KIAA1199 in cancer, Professor Brigitte Malgrange’s team on the congenital deafness aspect and Professor Malaise's team on the role of KIAA119 in rheumatoid arthritis”. Among other things, the researchers will generate mouse models where the gene coding for KIAA1199 will be inactivated so that they can address whether this genetic inactivation causes any delay in the development of mammary tumours or rheumatoid arthritis. “We think that in one way or the other, the connection with EGFR or with other members of this family is important in these three diseases. We are working on validating this assumption”, Alain Chariot concludes.

(1) Kateryna Shostak, Xin Zhang, Pascale Hubert, Serkan Ismail Göktuna, Zheshen Jiang, Iva Klevernic, Julien Hildebrand, Patrick Roncarati, Benoit Hennuy, Aurélie Ladang, Joan Somja, André Gothot, Pierre Close, Philippe Delvenne & Alain Chariot. NF-κB-induced KIAA1199 promotes survival through EGFR signalling. Nature communications| 5:5232 | DOI: 10.1038/ncomms6232 |