FUBP1 Promotes Colorectal Cancer Stemness and Metastasis via DVL1-Mediated Activation of Wnt/β-Catenin Signaling

Abstract Background: Most colorectal cancer (CRC) patients die from distant metastasis. Approximately 50% of CRC patients develop liver metastases, while 10% to 30% of patients appear pulmonary metastases. The occurrence of metastasis is considered to be almost exclusively driven by cancer stem cells (CSCs) formation. However, the key molecules that confer the stem-transformation of CRC and subsequent metastasis remain unclear.Methods: FUBP1 was screened in CRC CSCs by mass spectrometry and was examined by immunohistochemistry in a cohort of CRC tissues. The stemness induction and mechanism of FUBP1 were elucidated both in vivo and in vitro.Results: FUBP1 was upregulated in 85% of KRAS mutation and 25% of wildtype CRC patients which correspondence to the metastasis rate. Further, elevated FUBP1 was positively correlated with CRC lymph node metastasis and clinical stages and negatively associated with overall survival, whatever KRAS mutation or wildtype. Overexpression of FUBP1 significantly enhanced migration, invasion, tumor sphere formation and CD133/ALDH1 expression of CRC cells in vitro and the tumorigenicity in vivo. Mechanistically, FUBP1 promoted the initiation of CSCs by activating Wnt/β-catenin signaling via directly binding to the promoter of DVL1, a vigoroso activator of β-catenin. The knockdown of DVL1 tremendously blockaded the stem-transformation and tumorigenicity of CRC. Activation of Wnt/β-catenin signaling by DVL1 increased pluripotent transcription factors, including c-Myc, NANOG, SOX2 rather c-Myc alone. Moreover, FUBP1 was upregulated at the post-transcriptional level. Elevated FUBP1 in KRAS wildtype CRC patients is due to the decrease of Smurf2, which promotes ubiquitin-mediated degradation of FUBP1. Whereas FUBP1 was upregulated in mutated KRAS patients through both inhibition of caspase-3-dependent cleavage and decreased Smurf2.Conclusions: Our results demonstrate for the first time that FUBP1 is a novel oncogene for the initiation of CSCs as a new endogenous Wnt signaling powerful agonist and may provide an important prognostic factor and therapeutic target for metastasis in both KRAS mutation and wildtype CRC.