DUSP4 inhibits autophagic cell death and apoptosis in colorectal cancer by regulating BCL2-Beclin1/Bax signaling

Background The DUSP4 gene plays an important role in the carcinogenesis of colorectal cancer (CRC). However, the underlying mechanism of DUSP4-regulated colorectal carcinogenesis is unknown. DUSP4 is a negative regulator of the MAP kinase (MAPK) JNK, and JNK-mediated BCL2 phosphorylation is associated with apoptosis and autophagic cell death. Our study aimed to explore the significance of BCL2 phosphorylation-dependent autophagy and apoptosis in DUSP4-promoted colorectal carcinogenesis. Methods We first investigated the roles of DUSP4 in the survival of HCT116 and SW480 CRC cell lines using gene-silencing and -overexpression techniques. Next, we explored the effects of DUSP4 on the BCL2 phosphorylation, autophagy and apoptosis of HCT116 and SW480 cells. Ultimately, with the help of pharmacological inhibitors of Beclin1 and BCL2 (spautin-1 and ABT-737), the relationship between BCL2-Beclin1/Bax signaling and DUSP4-regulated autophagy, apoptosis, survival and migration in HCT116 cells was clarified. Results Our results first confirmed the contribution of DUSP4 to the survival of HCT116 and SW480 cells. In addition, DUSP4 silencing resulted in BCL2 phosphorylation and the enhancement in autophagy and apoptosis in HCT116 and SW480 cells, while DUSP4 overexpression showed the opposite effect. Moreover, DUSP4 silencing inhibited the protein interaction between BCL2 and Beclin1 or Bax in HCT116 cells. Moreover, the survival and migration of HCT116 cells inhibited by DUSP4 silencing were blocked by autophagy inhibition with spautin-1. Notably, the survival and migration of HCT116 cells promoted by DUSP4 overexpression were reversed by ABT-737. Conclusions It was indicated that DUSP4 can maintain the survival and function of CRC cells by inhibiting BCL2 phosphorylation-dependent autophagic cell death and apoptosis.