Epithelial cancers, also known as carcinomas, are the most common cancers worldwide. One protein that can either suppress or promote epithelial cancer progression is AnxA6, which is expressed in secretory tissues. However, it’s unclear whether changes to AnxA6 after translation determine its influence on cancer. To learn more, researchers recently investigated the role of SUMOylation, a modification involving attachment of a molecule called SUMO. They found that AnxA6 was indeed SUMOylated in cancer cell lines, and one key SUMOylation site was the lysine residue at position 299. SUMOylated AnxA6 helped inhibit cancer cell proliferation and migration by facilitating EGFR-PKCα complex formation and reducing activation of the tumor-promoting EGFR-ERK1/2/cyclin D1 pathway. Suppression of AnxA6 expression or mutation of the key AnxA6 SUMOylation site in epithelial cancer cells removed these effects and resulted in resistance to the anticancer drug gefitinib. Similarly, mice injected with AnxA6-deficient or AnxA6-mutant cancer cells grew smaller tumors than mice injected with non-manipulated cancer cells. Although more work is needed, the findings reveal that SUMOylation is an important mediator of AnxA6’s anticancer function and provide insights that may aid in the development of strategies to suppress cancer progression and combat drug resistance.