In reseach recently published in the Proc. Nat. Acad. Sci. U.S.A., graduate student Kiall Suazo in the Distefano Lab contributed to a collaborative project led by Professor Carol Williams in Medical College of Wisconsin in altering SmgGDS ratios using splice-switching strategy. SmgGDS has two isoforms (SmgGDS-607 and SmgGDS-558) that work together in prenylating and subsequent trafficking of a set of small GTPases. A high 607:558 ratio is implicated in cancer by supporting malignant phenotypes and tumor development. In an effort to reduce the ratio of SmgGDS-607 and SmgGDS-558 in a lung cancer model cell line, a splice-switch oligo nucleotide (SSO) was designed, which works by decreasing the amount of 607 and increasing 558.
Using a chemical proteomics approach developed in the Distefano lab, it was found that oncogenic small GTPases exhibited reduced prenylation upon SSO treatment, indicating that alteration of the SmgGDS ratio inhibits the prenylation of this subset of prenylated proteins. This observed reduce prenylation in cancer cells promotes ER stress, resulting suppressed tumor growth or induced cell death. Furthermore, the results from the proteomics study may have uncovered a novel aspect of SmgGDS intracellular function, linking the 607:558 ratio to the direct regulation and control of prenylation for other types of prenylation substrates. Indeed, this study exemplifies the power of chemical proteomic strategies to uncover aberrant levels of post-translationally modified proteins under perturbed conditions.