RGL2 Drives the Metastatic Progression of Colorectal Cancer via Preventing the Protein Degradation of β-Catenin and KRAS

SIMPLE SUMMARY: Aberrant activation of the Wnt/β-catenin pathway due to APC (adenomatous polyposis coli) loss and Kirsten ras (KRAS) mutation is highly associated with malignant evolution, e.g., metastasis, of colorectal cancer (CRC). Ral guanine nucleotide dissociation stimulator-like (RGL) proteins, such as RGL2, regulate RAS activity via controlling the exchange between GTP and GDP. Although the cross-talk between β-catenin and KRAS has been reported to promote cancer metastasis, the functional role of RGL2 remains largely unknown. Here we show that RGL2 is significantly upregulated in primary tumors compared to normal tissues and serves as a poor prognostic marker in CRC patients. Cell-based and animal experiments further demonstrate that RGL2 acts as a driver to promote the metastatic progression of CRC, most likely via preventing the protein degradation of β-catenin and KRAS. Our findings not only unveil the oncogenic function of RGL2 but also provide a new strategy to combat metastatic CRC by targeting RGL2 activity. ABSTRACT: Colorectal cancer (CRC) is one of the most common cancers and results in high mortality worldwide, owing to cancer progression, i.e., metastasis. However, the molecular mechanism underlying the metastatic evolution of CRC remains largely unknown. Here, we find that the upregulation of Ral Guanine Nucleotide Dissociation Stimulator Like 2 (RGL2) is commonly detected in primary tumors compared normal tissues and is significantly associated with a poorer prognosis in CRC patients. Moreover, RGL2 expression appeared to positively correlate with the metastatic potentials of CRC cells. Whereas RGL2 knockdown dramatically suppresses the metastatic potentials of CRC cells in vitro and in vivo, RGL2 overexpression in the poorly metastatic CRC cells and reconstitution in the RGL2-silenced CRC cells enhanced and rescued the cellular metastatic ability, respectively. Computational simulation using Gene Set Enrichment Analysis program and cell-based assays demonstrated that RGL2 expression causally associated with the activity of Wnt/β-catenin signaling axis and Kirsten ras (KRAS)S, as well as the progression of epithelial-mesenchymal transition (EMT) in the detected CRC cells. Importantly, RGL2 upregulation was capable of preventing the protein degradation of β-catenin and KRAS in CRC cells. These findings suggest that RGL2 acts as a driver to promote the metastatic progression of CRC and also serves as a poor prognostic biomarker in CRC patients.