FUBP1 promotes colorectal cancer stemness and metastasis via DVL1‐mediated activation of Wnt/β‐catenin signaling

• Published in: Molecular oncology Vol. 15; no. 12; pp. 3490 - 3512
• Main Authors: Yin, Haofan, Gao, Tianxiao, Xie, Jinye, Huang, Zhijian, Zhang, Xiaoyan, Yang, Fengyu, Qi, Weiwei, Yang, Zhonghan, Zhou, Ti, Gao, Guoquan, Yang, Xia
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-12-2021; John Wiley and Sons Inc; Wiley
• Subjects: Antibodies; beta Catenin - metabolism; Cancer; cancer stem cells; Caspase-3; Catenin; Cell activation; Cell cycle; Cell Line, Tumor; Cell migration; Cell Proliferation; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - pathology; Dishevelled protein; DNA binding proteins; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; FUBP1; Gene expression; Gene Expression Regulation, Neoplastic; Growth factors; Health aspects; Hepatocytes; Humans; Immunohistochemistry; K-Ras protein; Liver cancer; Lung cancer; Lymph nodes; Mass spectrometry; Mass spectroscopy; Metastases; Metastasis; Mutants; Myc protein; Neoplastic Stem Cells - pathology; Oncogenes; Patients; Pluripotency; Protein binding; Proteins; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Stem cells; Therapeutic targets; Transcription activation; Transcription factors; Tumorigenicity; Tumors; Ubiquitin; Ubiquitin-Protein Ligases - metabolism; Wnt protein; Wnt Signaling Pathway; China; United States > US; FUBP1; colorectal cancer; cancer stem cells
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.13064

Distant metastasis is, unfortunately, the leading cause of death in colorectal cancer (CRC). Approximately 50% of CRC patients develop liver metastases, while 10–30% of patients develop 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 transformation to stem cells in CRC, and subsequent metastasis, remain unclear. Far upstream element‐binding protein 1 (FUBP1), a transcriptional regulator of c‐Myc, was screened in CSCs of CRC by mass spectrometry and was examined by immunohistochemistry in a cohort of CRC tissues. FUBP1 was upregulated in 85% of KRAS‐mutant and 25% of wild‐type CRC patients. Further, whether in KRAS‐mutant or wild‐type patients, elevated FUBP1 was positively correlated with CRC lymph node metastasis and clinical stage, and negatively associated with overall survival. Overexpression of FUBP1 significantly enhanced CRC cell migration, invasion, tumor sphere formation, and CD133 and ALDH1 expression in vitro, and 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 potent activator of β‐catenin. Knockdown of DVL1 significantly inhibited the transformation to stem cells in, as well as the tumorigenicity of, CRC. Activation of Wnt/β‐catenin signaling by DVL1 increased pluripotent transcription factors, including c‐Myc, NANOG, and SOX2. Moreover, FUBP1 was upregulated at the post‐transcriptional level. Elevated FUBP1 levels in KRAS wild‐type CRC patients is due to the decrease in Smurf2, which promotes ubiquitin‐mediated degradation of FUBP1. In contrast, FUBP1 was upregulated in KRAS‐mutant patients through both inhibition of caspase 3‐dependent cleavage and decreased Smurf2. Our results demonstrate, for the first time, that FUBP1 is an oncogene, initiating the development of CSCs, as well as a new powerful endogenous Wnt‐signaling agonist that could provide an important prognostic factor and therapeutic target for metastasis in both KRAS‐mutant and wild‐type CRC.
Distant metastasis represents the leading cause of death in colorectal cancer (CRC). Cancer stem cells (CSCs) formation is considered to drive metastasis in patients with CRC; however, the key molecules guiding CSC formation remain elusive. Here, we investigated the role of the FUBP1 oncogene and DVL1, a novel agonist of endogenous Wnt signaling in CSCs development. Our data indicate that FUBP1 acts in initiating the development of CSC and could serve as a prognostic factor, as well as a potential therapeutic target in both KRAS‐mutant and wild‐type patients with CRC metastasis.