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S-Nitrosylation of DNMTs in epigenetic regulation of tumors

Institution: Scripps Research Institute
Investigator(s): Stuart Lipton, M.D., Ph.D.
Award Cycle: 2018 (Cycle 27) Grant #: 27IR-0010 Award: $1,448,303
Subject Area: Cancer
Award Type: High Impact Research Project Award

Initial Award Abstract

Tobacco is known to induce aberrantly high levels of the free radical gas called nitric oxide (NO), and to contribute to 17 forms of cancer. Our group discovered that NO can bind to cysteine amino acids in proteins, a reaction called S-nitrosylation, thereby modifying protein function. High levels of NO can cause aberrant protein function in this manner. Here, we demonstrate that S-nitrosylation of an important protein called DNA methyltransferase can alter its function of regulating many genes.  In this manner, overproduction of NO in cancer cells, causing S-nitrosylation of DNMT3B, can exert a deleterious effect on gene expression and thus abnormally alter cell function and contribute to cancer formation.

We next screened libraries of drug-like compounds for a molecule that could block S-nitrosylation of DNMT3B. We found a candidate, designated DBIC, that could prevent the aberrant S-nitrosylation of DNMT3B. Importantly, we then found that treatment with DBIC also completely blocked cancerous transformation induced by NO in two strains of human cancer cells and in an in vivo model of cancer in mice, indicating that the drug could block tumor formation.

In this proposal, we will first determine if S-nitrosylation of DNA methyltransferases (forming SNO-DNMTs) occurs in human tumors associated with tobacco use. We will analyze as many types of tumors as possible that are known to be associated with tobacco use. Second, we will determine the mechanism and causal role of SNO-DNMT3B in tobacco-associated tumor proliferation. These experiments will be performed by assessing the proliferation of cancer cells in the presence of a mutated form of DNMT3B that cannot be S-nitrosylated (accomplished by substituting and alanine amino acid for the critical cysteine amino acid that would otherwise by S-nitrosylated).  Because this cysteine residue is critical for the enzymatic activity of DNMT3B, we posit that this mutation should mimic the effect of S-nitrosylation in inhibiting the function of DNMT3B; hence, the non-nitrosylatable mutant form of DNMT3B should result in increased cancer cell proliferation if our hypothesis is correct. Third, we will test compounds, including DBIC, which we have found through our screening efforts that prevent S-nitrosylation of DNMT3B, in an effort to develop a lead candidate toward a drug that can inhibit cancer cell proliferation by blocking the S-nitrosylation of DNMT3B.

In summary, our planned research is relevant to lung and other types of human cancers that are known to be related to tobacco use. We have discovered a novel chemical reaction, called protein S-nitrosylation, that is triggered by tobacco-generation of NO, and regulates the proliferation of cancer cells by inhibiting an enzyme named DNMT3B. We are now developing drug candidates to suppress cancer growth by inhibiting the unique chemical reaction of S-nitrosylation on DNMT3B.  Such a drug, if sufficiently selective in its activity, would block cancer cell proliferation and spread without unwanted side effects and thus, provide a great benefit for the population of California and the world.