Gastric cancer is one of the
cancers with high morbidity and mortality worldwide. The aryl
sulfonamide indisulam inhibits the proliferation of several types of
cancer cells through its function as a molecular glue to promote the ubiquitination and degradation of RNA-binding motif
protein 39 (RBM39). However, it is unknown whether and how
indisulam regulates the migration of
cancer cells. In this work, using label-free quantitative proteomics, we discover that
indisulam significantly attenuates
N-cadherin, a marker for epithelial to mesenchymal transition and migration of
cancer cells. Our bioinformatics analysis and biochemical experiments reveal that
indisulam promotes the interaction between the
zinc finger E-box-binding homeobox 1 (ZEB1), a
transcription factor of
N-cadherin, and DCAF15, a substrate receptor of CRL4
E3 ubiquitin ligase, and enhances ZEB1 ubiquitination and proteasomal degradation. In addition, our cell line-based experiments demonstrate that
indisulam inhibits the migration of
gastric cancer cells in a ZEB1-dependent manner. Analyses of patient samples and datasets in public databases reveal that
tumor tissues from patients with
gastric cancer express high ZEB1
mRNA and this high expression reduces patient survival rate. Finally, we show that treatment of gastric
tumor samples with
indisulam significantly reduces ZEB1
protein levels. Therefore, this work discloses a new mechanism by which
indisulam inhibits the migration of
gastric cancer cells, indicating that
indisulam exhibits different
biological functions through distinct signaling molecules.