Through a RNAi synthetic lethal screen we have identified the protein SUMOylation pathway to be required for the viability and transformation of Ras mutant cancer cells. PURPOSE. In this project we aim to address the following questions: 1) the mechanism by which inhibition of SUMO ligases is synthetically lethal with the KRAS oncogene;2) which cellular proteins are differentially SUMOylated in Ras mutant cells;and 3) How the changes in SUMOylation status of these proteins affect their function in the context of Ras mutant tumors. SIGNIFICANT MATERIALS AND METHODS. 1) shRNAs that target the SUMO E1 and E2 ligases and SUMO pathway proteins;2) Stable cell lines expressing SUMO proteins and ligases;3) mass-spectrometry methodology for identifying SUMOylated proteins in cell lysates. FY2014 ACCOMPLISHMENT. We have validated the role of SUMO ligases in KRAS driven transformation and we have identify a mechanism by which this occurs. We have identified cellular proteins that are differentially SUMOylated in association with KRAS mutation and we are investigating how these SUMOylation events affect the function of these proteins, and how they in turn support KRAS driven transformation. A manuscript describing our findings has been submitted for publication.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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Zhang, Haibo; Luo, Ji (2016) SUMO wrestling with Ras. Small GTPases 7:39-46
Ma, Chi; Kesarwala, Aparna H; Eggert, Tobias et al. (2016) NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531:253-7
Yu, Bing; Swatkoski, Stephen; Holly, Alesia et al. (2015) Oncogenesis driven by the Ras/Raf pathway requires the SUMO E2 ligase Ubc9. Proc Natl Acad Sci U S A 112:E1724-33
Kessler, Jessica D; Kahle, Kristopher T; Sun, Tingting et al. (2012) A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science 335:348-53
Weng, Meng-Tzu; Lee, Jih-Hsiang; Wei, Shu-Chen et al. (2012) Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells. Proc Natl Acad Sci U S A 109:E3659-67