Downregulation of STK4 promotes colon cancer invasion/migration through blocking β-catenin degradation.

Mammalian STE20-like kinase 1 (MST1/STK4/KRS2) encodes a serine/threonine kinase that is the mammalian homolog ofDrosophilaHippo. STK4 plays an important role in controlling cell growth, apoptosis, and organ size. STK4 has been studied in many cancers with previous studies indicating an involvement in colon cancer lymph node metastasis and highlighting its potential as a diagnostic marker for colon cancer. However, the role of STK4 defect in promoting colon cancer progression is still understudied. Here, we found that STK4 was significantly downregulated in colon cancer and was associated with distal metastasis and poor survival. Furthermore, STK4 knockdown enhanced sphere formation and metastasisin vitroand promoted tumor developmentin vivo. We found that STK4 colocalized with beta-catenin and directly phosphorylated beta-catenin resulting in its degradation via the ubiquitin-mediated pathway. This may suggest that STK4 knockdown causes beta-catenin phosphorylation failure and subsequently beta-catenin accumulation, consequently leading to anchorage-independent growth and metastasis in colon cancer. Our results support that STK4 may act as a potential candidate for the assessment of beta-catenin-mediated colon cancer prognosis.