Post-translational modifications by the small ubiquitin-like modifier (SUMO) family are important in oncogenesis and cellular response to DNA damage. Recent findings indicate that the key oncogenic pathways driven by Myc and KRas are dependent on, or addicted to, SUMOylation. In one study, genome-wide siRNA knockdown identified the gene encoding the catalytic subunit of the SUMO activating enzyme (SAE), SAE2, as having the strongest synthetic lethal interaction with Myc hyperactivation. Similarly, genes encoding the SUMOylation enzymes were found to be critical for KRas-dependent tumorigenesis. Based on these findings, we hypothesize that the SAE is a novel target for developing anti-cancer therapeutics for cancers that are Myc-and KRas-dependent. The over-arching goal of this proposal is to test this hypothesis, and the proposed studies are enabled by our discovery of potent and specific SAE inhibitors that have selective toxicity to cancer cell lines that have high Myc-expression levels and/or KRas mutation. We propose to investigate the molecular mechanisms underlying the synthetic lethality of SUMOylation with Myc hyperactivation and KRas mutations in order to further validate the SAE as a potential cancer therapeutic target. In addition, we will investigate the structure-activity relationship of how the inhibitors interact with the SAE and inhibit its enzymatic activity, and use this information to guide further improvement of the inhibitors. These studies could potentially improve treatment of many cancers, as overexpression of Myc is estimated to contribute to 70% of all human cancers, and KRas is also frequently mutated in human cancers. However, both Myc and KRas have proven difficult to inhibit pharmacologically. Thus, the proposed studies will likely establis a new paradigm to target the SAE for the development of novel cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM086171-06
Application #
8595315
Study Section
Special Emphasis Panel (ZRG1-BMCT-C (09))
Program Officer
Janes, Daniel E
Project Start
2008-04-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
6
Fiscal Year
2014
Total Cost
$282,844
Indirect Cost
$152,235
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Namanja, Andrew T; Wang, Jianghai; Buettner, Ralf et al. (2016) Allosteric Communication across STAT3 Domains Associated with STAT3 Function and Disease-Causing Mutation. J Mol Biol 428:579-89
Du, Li; Li, Yi-Jia; Fakih, Marwan et al. (2016) Role of SUMO activating enzyme in cancer stem cell maintenance and self-renewal. Nat Commun 7:12326
Fong, Miranda Y; Zhou, Weiying; Liu, Liang et al. (2015) Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol 17:183-94
Alontaga, Aileen Y; Ambaye, Nigus D; Li, Yi-Jia et al. (2015) RWD Domain as an E2 (Ubc9)-Interaction Module. J Biol Chem 290:16550-9
Madu, Ikenna G; Li, Shirley; Li, Baozong et al. (2015) A Novel Class of HIV-1 Antiviral Agents Targeting HIV via a SUMOylation-Dependent Mechanism. Sci Rep 5:17808
Alontaga, Aileen Y; Li, Yifei; Chen, Chih-Hong et al. (2015) Design of high-throughput screening assays and identification of a SUMO1-specific small molecule chemotype targeting the SUMO-interacting motif-binding surface. ACS Comb Sci 17:239-46
Chen, Chih-Hong; Namanja, Andrew T; Chen, Yuan (2014) Conformational flexibility and changes underlying activation of the SUMO-specific protease SENP1 by remote substrate binding. Nat Commun 5:4968
Wang, Jiin-Tarng; Xu, Xiaohua; Alontaga, Aileen Y et al. (2014) Impaired p32 regulation caused by the lymphoma-prone RECQ4 mutation drives mitochondrial dysfunction. Cell Rep 7:848-58
Madu, Ikenna G; Namanja, Andrew T; Su, Yang et al. (2013) Identification and characterization of a new chemotype of noncovalent SENP inhibitors. ACS Chem Biol 8:1435-41
Truong, Khue; Lee, Terry D; Li, Baozong et al. (2012) Sumoylation of SAE2 C terminus regulates SAE nuclear localization. J Biol Chem 287:42611-9

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