P14 - An integrated approach for drug target validation
Distant metastasis is the major cause of cancer related death. Low RAI2 gene expression was initially identified at ITB/UCCH to be correlated with poor patient survival and in particular with the detection of disseminated tumor cells in the bone marrow of patients that were otherwise free of overt metastases. So far, the RAI2 protein function has not been annotated; but joint efforts of the applicant and the research team at EMBL funded by DFG have already shown that this protein acts as transcriptional co-regulator and that its inactivation in breast cancer cells directly leads and to dedifferentiation and deregulation of hormone response (PMID: 25716347).
More recently, both research teams showed that RAI2 binding to CtBP counteracts its oncogenic activity. Using VCaP prostate cancer cells as model, we show that RAI2-driven CtBP polymerization sustains epithelial differentiation. We hypothesize that RAI2 mediated negative CtBP regulation might be exploited to treat cancer patients more efficiently. The major aim of the proposed project is to validate the potential of RAI2-mediated CtBP inactivation as new therapeutic concept using their integrated drug target validation approach.
Partner: Prof. Matthias Wilmanns, EMBL Hamburg
Grants: MSNZ-Hamburg, Deutsche Krebshilfe
Contact: st.werner@uke.de
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Selected publications on topic
Expression Patterns and Corepressor Function of Retinoic Acid-induced 2 in Prostate Cancer. Besler K, Węglarz A, Keller L, von Amsberg G, Bednarz-Knoll N, Offermann A, Stoupiec S, Eltze E, Semjonow A, Boettcher L, Schneegans S, Perner S, Hauch S, Todenhöfer T, Peine S, Pantel K, Wikman H, Werner S.Clin Chem. 2022 Jul 3;68(7):973-983. doi: 10.1093/clinchem/hvac073.PMID: 35652463
1H, 13C, and 15N backbone assignments of the C-terminal region of the human retinoic acid-induced protein 2. Lang A, Goradia N, Wikman H, Werner S, Wilmanns M, Ohlenschläger O.Biomol NMR Assign. 2020 Oct;14(2):271-275. doi: 10.1007/s12104-020-09960-9. Epub 2020 Jun 18.PMID: 32557393
Suppression of early hematogenous dissemination of human breast cancer cells to bone marrow by retinoic Acid-induced 2. Werner S, Brors B, Eick J, Marques E, Pogenberg V, Parret A, Kemming D, Wood AW, Edgren H, Neubauer H, Streichert T, Riethdorf S, Bedi U, Baccelli I, Jücker M, Eils R, Fehm T, Trumpp A, Johnsen SA, Klefström J, Wilmanns M, Müller V, Pantel K, Wikman H.Cancer Discov. 2015 May;5(5):506-19. doi: 10.1158/2159-8290.CD-14-1042. Epub 2015 Feb 25.PMID: 25716347
