Die neue Lysin-methyltransferase ILSE1 kontrolliert das Wachstum des hormonrefraktären Prostatakarzinoms

• Antragsteller: Professor Dr. Roland Schüle
• Fachliche Zuordnung: Reproduktionsmedizin, Urologie
• Förderung: Förderung von 2018 bis 2022
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 389637042

Epigenetic writers such as histone methyltransferases play key roles in the control of physiology and pathology. Consequently, small molecule inhibitors of various histone methyltransferases have been developed and entered clinical evaluation. To further expand our knowledge on the molecular functions of this important class of epigenetic enzymes we combined bioinformatic approaches such as homology prediction and cheminformatics with 3D structural information to identify novel histone methyltransferases (HMTs) with putative clinical relevance. One of the interesting lysine methyltransferases, hereafter named ILSE1 presents as an epigenetic enzyme writing the chromatin mark histone H4 monomethylated at lysine 12 (H4K12me) to which no function has been assigned so far. Introduction of a single point mutation in the catalytic center or treatment with the S-adenosyl methionine (SAH)-competitive inhibitor sinefungin abrogates methylation by ILSE1 in vitro. Accordingly, depletion or ectopic expression of ILSE1 results in reduced and elevated H4K12me levels in cultured cells, respectively. Of note, ILSE1 RNAi most robustly impairs proliferation of both androgen-dependent and castration-resistant prostate cancer cell lines. In contrast, growth of non-transformed cells and various other tumor cells is not regulated by ILSE1 uncovering unprecedented specificity of action. Finally, depletion of ILSE1 results in severely retarded growth of androgen-dependent and castration-resistant prostate cancer cell in mouse xenograft models. In summary, our preparatory work demonstrates that ILSE1 is the first H4K12 methyltransferase robustly impairing proliferation of castration-resistant prostate cancer in vitro and in vivo. Thus, our data identify ILSE1 as a target for potential therapeutic intervention of castration-resistant prostate cancer by small molecule inhibitors. Consequently, we propose to (1) determine the 3D crystal structure of ILSE1 and use the structural information to design and characterize chemical probes that inhibit ILSE methyltransferase activity. We shall (2) unravel the function of ILSE1 in physiology and pathology by the identification and characterization of target genes. Finally, we plan to (3) determine how the information stored in the chromatin mark H4K12me is interpreted and transduced into physiological and pathological traits by characterization of reader and eraser proteins.

• DFG-Verfahren: Sachbeihilfen