CDK15 promotes colorectal cancer progression via phosphorylating PAK4 and regulating ß-catenin/ MEK-ERK signaling pathway.

Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer-related deaths. However, there are few effective therapeutic targets for CRC patients. Here, we found that CDK15 was highly expressed in human CRC and negatively correlated with patient prognosis and overall survival in tissue microarray. Knockdown of CDK15 suppressed cell proliferation and anchorage-independent growth of CRC cells and inhibited tumor growth in cell line-derived xenograft (CDX) model. Importantly, knockout of CDK15 in mice retarded AOM/DSS-induced tumorigenesis and CDK15 silencing by lentivirus significantly suppressed tumor progression in patient-derived xenograft (PDX) model. Mechanistically, CDK15 could bind PAK4 and phosphorylate PAK4 at S291 site. Phosphorylation of PAK4 at the S291 residue promoted cell proliferation and anchorage-independent growth through ß-catenin/c-Myc, MEK/ERK signaling pathway in CRC. Moreover, inhibition of PAK4 reversed the tumorigenic function of CDK15 in CRC cells and pharmacological targeting PAK4 suppressed tumor growth in PDX models. Thus, our data reveal the pivotal role of CDK15 in CRC progression and demonstrate CDK15 promotes CRC tumorigenesis by phosphorylating PAK4. Hence, the CDK15-PAK4 axis may serve as a novel therapeutic target for CRC.