Importance of SUMOylation Consensus Sequence of MAFK in Regulating EMT, Tumor Growth, Stemness, and Drug Resistance

Posttranslational modification is crucial for modulating protein functions. SUMOylation is a posttranslational modification where a small ubiquitin-related (like) modifier (SUMO) conjugates to a lysine residue in the substrate proteins. SUMOylation has been shown to affect the alteration of substrate proteins' functions, subcellular localization, or stability. Furthermore, it has been reported that SUMOylation is involved in regulating angiogenesis, cellular migration, and epithelial-mesenchymal transition (EMT). Moreover, a link between SUMO proteins and multidrug resistance in hepatocellular carcinoma and multiple myeloma has been reported. Classified as a set of transcription factors belonging to the basic region leucine zipper (bZIP) family, musculoaponeurotic fibrosarcoma (MAF) proteins are divided into two groups: large MAF (c-MAF, MAFA, and MAFB) and small MAF (MAFF, MAFG, and MAFK). We previously demonstrated that MAFK confers tumorigenic ability to nontumorigenic mammary gland epithelial cells, NMuMG cells, through induction of EMT. Furthermore, the knockdown of MAFK significantly suppressed the tumorigenic and metastatic growth of breast cancer cells. Among MAF family proteins, the SUMOylation consensus sequence, ψKxE, is highly conserved, and SUMOylation has been shown in MAF family proteins, MAFB and MAFG, respectively. In this study, we focused on SUMOylation and investigated the importance of the SUMOylation consensus sequence in MAFK for MAFK-induced EMT, cellular migration and invasion, tumor and sphere formation, acquisition of stem-like properties, and drug resistance against doxorubicin by using the non-SUMOylation mimic mutant. Additionally, our results suggest that these findings depend on the expression of ATP-binding cassette (ABC) transporter 2 (ABCG2).