Characterization of genes involved in chromatin remodeling complexes and their functional role in hepatocarcinogenesis.

• Applicant: Dr. Kornelius Schulze
• Subject Area: Gastroenterology ; Cell Biology
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 247753630

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide. Next to environmental risk factors, genetic alterations are considered to modulate the multi-step process in HCC development. In a recent project, Zucman-Rossi et al. have identified alterations in genes encoding chromatin remodeling complexes. Mutations in ARID1A/ARID2 (AT-rich interactive domain-containing protein), subunits of chromatin remodeling complexes, have been most frequent. In several other tumor entities, e.g. gastric, ovarian, and bladder cancer, ARID1A is inactivated and has been identified to confer tumor suppressor functions. Further research by exome sequencing has also revealed mutations in additional chromatin remodeling genes, so that in total, greater than 24% of HCC samples show mutations in at least one gene related to chromatin remodeling complexes. Based on these and other observations, we hypothesize that alterations in chromatin remodeling complexes are a major contributor to hepatocarcinogenesis, requiring further validation and characterization as well as functional analyses of consequences. In this project, we will initially validate mutations in genes participating in chromatin remodeling in a large set of HCC tissue samples. Following validation, correlations to clinical features will be investigated. Differences in molecular cell regulation between ARID1A/ARID2-mutated and -non-mutated tumors will be studied by transcriptome analysis. To further understand the functional roles of chromatin remodeling complexes and, more specifically, of ARID1A/ARID2 in tumor cell activity, we will perform ectopic expression/silencing of ARID1A/ARID2 and characterize subsequent consequences in hepatocyte cancer cell models. To determine whether silencing of ARID1A/ARID2 in hepatocyte cancer cell lines will have an effect on tumor growth, an evaluation of invasiveness, and expression of hepatic stem cell markers is proposed in a subcutaneous xenograft mouse model. Based on obtained data, we will evaluate putative pharmacological treatment strategies by direct interaction of chromatin remodeling complexes as well as intracellular target proteins.

• DFG Programme: Research Fellowships
• International Connection: France
• Host: Professorin Jessica Zucman-Rossi, Ph.D.