We and others have previous shown that the SUMO pathway to play an important role in supporting the viability and transformation growth of KRAS mutant cancer cells. The molecular mechanism underlying this process is not fully understood. PURPOSE. In this project we aim to study the following questions: 1) the mechanism by which the SUMO pathway supports cellular transformation driven by the KRAS oncogene; 2) cellular proteins that are differentially SUMOylated in Ras mutant cells; and 3) cellular pathways that are co-regulated by the Ras and the SUMO pathways. SIGNIFICANT MATERIALS AND METHODS. 1) shRNA and CRISPR/Cas9 reagents that target SUMO ligases and SUMO pathway proteins; 2) stable cell lines expressing SUMO ligases and SUMO substrate proteins; 3) mass-spectrometry methodology for identifying SUMOylated proteins in cell lysates. ACCOMPLISHMENT. We discovered that KRAS mutant colorectal cancer cells exhibit altered patterns of protein SUMOylation and Ras driven transformation requires SUMO E2 ligase activity. We are currently investigating transcription factors that are SUMO substrates for their roles in KRAS transformation. We are also exploring potential methods for developing inhibitors targeting the SUMO pathway.
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