Abstract
A disintegrin and metalloproteinase (ADAM) family of proteins play versatile roles in cancer development and progression. In the present study, we investigated the role of ADAM proteins in colorectal cancer (CRC) cell migration and invasion focusing on the epigenetic mechanism whereby ADAM transcription is regulated. We report that higher levels of ADAM10, ADAM17, and ADAM19 were detected in SW480 cells than in HCT116 cells. Expression levels of the same set of ADAMs were higher in human CRC biopsy specimens of advanced stages than in those of a less aggressive phenotype. Overexpression of ADAM10/17/19 in HCT116 cells enhanced, whereas depletion of ADAM10/17/19 in SW480 cells weakened, migration and invasion. ADAM expression was activated by the Wnt signaling pathway, which could be attributed to direct binding of β-catenin on the ADAM promoters. Mechanistically, β-catenin recruited the chromatin remodeling protein BRG1, which in turn enlisted histone demethylase KDM4 to alter the chromatin structure, thereby leading to ADAM transactivation. In conclusion, our data suggest that the Wnt signaling may promote CRC metastasis, at least in part, by recruiting an epigenetic complex to activate ADAM transcription.
Highlights
Colorectal cancer (CRC) represents one of the deadliest forms of cancers worldwide with approximately 2 million projected new diagnoses each year (Bray et al, 2018)
ADAM10, ADAM17, and ADAM19 were significantly up-regulated in SW480 cells compared to HCT116 cells
It was noted that elevated expression levels of BRG1, a chromatin remodeling protein, were detected in SW480 cells compared to HCT116 cells (Figures 1A,B), in the tumorous tissues compared to the adjacent tissues (Figure 1C), and in the highly malignant tumors compared to the lesser malignant tumors (Figure 1D), all consistent with the expression patterns of A disintegrin and metalloproteinase (ADAM)
Summary
Colorectal cancer (CRC) represents one of the deadliest forms of cancers worldwide with approximately 2 million projected new diagnoses each year (Bray et al, 2018). Implementation of early screening, advancement of surgical techniques, and personalized chemotherapeutic medications have considerably alleviated the mortality and morbidity of CRC patients. These β-Catenin Regulates ADAM Transcription improvements in CRC prevention and intervention notwithstanding, disease-free survival rate for patients diagnosed with advanced stages of CRC remains dreadfully low, with more than 800,000 CRC patients succumbing to this malicious disease in 2018 alone (Araghi et al, 2019). Β-catenin enhances the mobility of metastasizing cancer cells by activating the transcription of a panel of different metalloproteinases (MMPs) to contribute to the remodeling of the extracellular matrix (Lowy et al, 2006; Kamino et al, 2011; Yang F. et al, 2019). Regulation of MMPs by several mechanisms including transcriptional activation via promoter and via miRNAs plays important roles in the remodeling of extracellular matrix (Surgucheva et al, 2003; Surgucheva et al, 2010)
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