Role of lysine methyltransferase SMYD2-dependent methylation and identification of new Smyd2 related pathways in pancreatic ductal adenocarcinoma

• Applicant: Dr. Julia Arand
• Subject Area: General Genetics and Functional Genome Biology ; Cell Biology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 249161259

Post-translational modifications can change the properties of proteins significantly and thus regulate cellular processes in a large network, as it has been shown for histone modifications regulating chromatin structure. The lysine methyltransferase SMYD2 is thought to methylate histones and might therefore contribute to the epigenetic code. SMYD2 is also responsible for methylating other cellular proteins, such as the tumor suppressors p53 and RB. SMYD2 is overexpressed in many human tumors, among these pancreatic ductal adenocarcinoma (PDAC). PDAC is often diagnosed very late and curability is very low. The goal of my proposed research project is to understand the role of SMYD2 in PDAC and to identify SMYD2 targets, which may have considerable effect on tumorigenesis and tumor maintenance. I will use a mouse model, in which PDAC is induced by activation of oncogenic Kras. Kras is mutated in more than 90% of all PDACs. Analysing the knockout of Smyd2 in this system, I will test the influence of the mouse Smyd2 protein on tumorigenesis. These experiments will be complemented by the analysis of human pancreatic cell lines depleted for SMYD2 to analyse the effect on tumor maintenance. Since the substrates that are methylated by SMYD2 are not yet completely known and first experiments in mice show that Smyd2 has effects on tumorigenesis independent on p53, I will use two different strategies, which will allow me to analyse SMYD2 targets in vivo. The first strategy is based on the enrichment of methylated proteins, which will be differentially labelled dependent on cells expressing SMYD2or a catalytically inactive form of SMYD2. The second strategy is based on an engineered SMYD2, which specifically uses a SAM analog and will transfer an alkyne group instead of a methylgroup to the substrate. The alkyne group will be used to isolate the specific substrates of SMYD2. The identified targets will be tested for their oncogenic or tumor suppressive function. Understanding the role of SMYD2 and identifying new substrates of SMYD2, which are key players in PDAC tumorigenesis and maintenance, will illuminate basic mechanisms that are crucial for pancreatic tumor cells and will identify novel pathways as a new starting point for the therapy and diagnosis of PDAC and other related cancer types.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Julien Sage