Metastasis, the main lethal course in cancer patients, is a process during which tumor cells transfer from the primary site to another non-adjacent site. Several proteins play as enhancers or suppressors in the regulation of cancer metastasis. Slug, a member of Snail transcription factor family, promotes cancer cell invasiveness through transcriptional repression of its target genes containing E-box DNA-binding sequence, such as E-cadherin, or through the upregulation of MMP-2 enzyme activity. However, the exact mechanisms of the modulation of Slug protein are still unclear. In this study, we presented sumoylation as a novel mechanism that regulates Slug post-translationally. By yeast two-hybrid screening, we identified the E2 SUMO-conjugating enzyme, Ubc9, and small ubiquitin-like modifier (SUMO)-1 as a Slug-interacting protein. Residues 130~212 of Slug interacts with Ubc9. In addition, we demonstrated that Slug could be covalently modified by SUMO-1 in vivo and in vitro. Furthermore, site-directed mutagenesis identifies several lysine residues as the sumoylation sites on Slug. Moreover, overexpression of UBC9 or SUMO-1 protein could affect the distribution of Slug. Thus, the sumoylation of Slug may affect its transcriptional activity or cellular functions. In conclusion, we provide another possible regulatory mechanism by which Slug mediates cancer metastasis.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4948.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO