Dual-Specificity Phosphatase 4 Promotes Malignant Features in Colorectal Cancer Through Cyclic-AMP Response Element Binding Protein/Protein Kinase CAMP-Activated Catalytic Subunit Beta Activation

Introduction: Previous studies have demonstrated that Dual-specificity Phosphatase 4 (DUSP4) plays an important role in the progression of different tumor types. However, the role and mechanism of DUSP4 in colorectal Cancer (CRC) remain unclear.

Aims: We investigate the role and mechanisms of DUSP4 in CRC.

Methods: Immunohistochemistry was used to investigate DUSP4 expression in CRC tissues. Cell proliferation, Apoptosis and migration assays were used to validate DUSP4 function in vitro and in vivo. RNA-sequence assay was used to identify the target genes of DUSP4. Human phosphokinase array and inhibitor assays were used to explore the downstream signaling of DUSP4.

Results: DUSP4 expression was upregulated in CRC tissues relative to normal colorectal tissues, and DUSP4 expression showed a significant positive correlation with CRC stage. Consistently, we found that DUSP4 was highly expressed in colorectal Cancer cells compared to normal cells. DUSP4 knockdown inhibits CRC cell proliferation, migration and promotes Apoptosis. Furthermore, the ectopic expression of DUSP4 enhanced CRC cell proliferation, migration and diminished Apoptosis in vitro and in vivo. Human phosphokinase array data showed that ectopic expression of DUSP4 promotes CREB activation. RNA-sequencing data showed that PRKACB acts as a downstream target gene of DUSP4/CREB and enhances CREB activation through PKA/cAMP signaling. In addition, xenograft model results demonstrated that DUSP4 promotes colorectal tumor progression via PRKACB/CREB activation in vivo.

Conclusion: These findings suggest that DUSP4 promotes CRC progression. Therefore, it may be a promising therapeutic target for CRC.

Apoptosis; Colorectal cancer; DUSP4; Migration; PRKACB/CREB; Proliferation.