PAK5 promotes RNA helicase DDX5 sumoylation and miRNA-10b processing in a kinase-dependent manner in breast cancer.

P21-activated kinase 5 (PAK5) plays an important role in tumors. However, the functional role of PAK5 in mammary tumorigenesis in vivo remains unclear. Here, we show that PAK5 deficiency represses MMTV-PyVT -driven breast tumorigenesis. DEAD-box RNA helicase 5 (DDX5) is a substrate of PAK5, which is phosphorylated on threonine 69. PAK5-mediated DDX5 phosphorylation promotes breast cancer cell proliferation and metastasis. The increased expression levels of PAK5 and phospho-DDX5 threonine 69 are associated with metastasis and poor clinical outcomes of patients. PAK5 facilitates the phosphorylation-dependent sumoylation of DDX5 to stabilize DDX5. Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing. Finally, we verify decreased expression of DDX5 phosphorylation and sumoylation and mature miR-10b in PAK5 ^−/− /MMTV-PyVT transgenic mice. Our findings provide insights into the function of PAK5 in microRNA (miRNA) biogenesis, which might be a potential therapeutic target for breast cancer. [Display omitted] • PAK5 deficiency represses MMTV-PyVT- driven mammary tumorigenesis • PAK5-mediated DDX5 phosphorylation enhances DDX5 sumoylation and stability • PAK5 enhances the formation of the DDX5/Drosha/DGCR8 complex leading to mature miR-10b • High expression of PAK5 and p-DDX5 is associated with poor outcomes of breast cancer Li et al. show that PAK5 deletion suppresses mammary tumorigenesis in MMTV-PyVT transgenic mice, an effect that is related to the PAK5-DDX5-miR-10b pathway. Phosphorylation-dependent sumoylation of DDX5 by PAK5 enhances formation of a DDX5/Drosha/DGCR8 complex, thus promoting miR-10b processing posttranscriptionally, suggesting a potential therapeutic avenue for breast cancer treatment. [ABSTRACT FROM AUTHOR]