Die Rolle der Histon-Demethylase KDM5C in metastatischem Prostatakarzinom
Zusammenfassung der Projektergebnisse
Prostate cancer (PCa) poses a major public health problem in men. Metastatic PCa is incurable, and ultimately threatens the life of many patients. The events that lead to metastatic prostate cancer are still enigmatic and no curative treatment is available yet. Therefore novel therapeutic concepts are ultimately needed. Modulating the activities of histone demethylases and/or demethylase controlling signaling proteins is an innovative therapeutic concept to block tumor growth. The histone demethylase KDM5C exerts important roles in tumorigenesis. KDM5C has been reported to be highly expressed in various cancer cell types, particularly in primary PCa. We could show that KDM5C is highly upregulated in metastatic PCa. Functionally, in KDM5C knockdown cells migratory and invasion capacity was reduced. Interestingly, modulation of KDM5C expression influences several EMT signaling pathways (e.g. Akt/mTOR), expression of EMT transcription factors, epigenetic modifiers, and miR-205, resulting in increased expression of E-cadherin and reduced expression of N-cadherin. Finally, depletion of KDM5C results in severely retarded growth prostate cancer cell in mouse xenograft models. In addition, the Akt/mTOR pathway is one of the classic signaling pathways to mediate tumor metabolic homeostasis, which is beneficial for tumor growth and metastasis. To conclude, our findings indicate that a combination of a selective KDM5C- and Akt/mTOR-inhibitor might be a new promising therapeutic strategy to reduce metastatic burden in PCa. In the second part of the study, we identified KDM5C-containing complexes by combing proteomic and bioinformatic approaches. By Tandem Affinity Purification followed by mass spectrometry, we could identify 49 proteins interacting with KDM5C. Several interacting proteins were expressed in PCa and we demonstrated by IHC their increase during progression of prostate cancer. Further experiments will characterize signaling mechanisms that modify KDM5C and analyze the consequences of these modifications on biological function, especially tumor metastasis. Clearly, the future impact of this work will deliver novel insights into epigenetic pathways and mechanisms in prostate cancer progression and ultimately will provide novel therapeutic targets, concepts and biomarkers, and have the potential as starting points for the development as therapeutic interventions.
Projektbezogene Publikationen (Auswahl)
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Histone Demethylase KDM5C Drives Prostate Cancer Progression by Promoting EMT. Cancers, 14(8), 1894.
Lemster, Anna-Lena; Sievers, Elisabeth; Pasternack, Helen; Lazar-Karsten, Pamela; Klümper, Niklas; Sailer, Verena; Offermann, Anne; Brägelmann, Johannes; Perner, Sven & Kirfel, Jutta
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Identifying proteins interacting with KDM5C in prostate cancer, Presentation: 105. Jahrestagung der Deutschen Gesellschaft für Pathologie 2022
Lemster A.L., Rezaienia M., Lazar-Karsten P., Gresens L., Sylvester M., Perner S. & Kirfel J.
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The role of histone demethylase KDM5C in metastatic prostate cancer. Presentation: 104. Jahrestagung der Deutschen Gesellschaft für Pathologie 2020
Lemster A.L., Pasternack H., Sievers E., Brägelmann J., Klümper N., Offermann A., Perner S. & Kirfel J.
