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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
P300 increases CSNK2A1 expression which accelerates colorectal cancer progression through activation of the
1Tumor Surgical Department, Beijing Chuiyangliu Hospital, No.2, Chuiyangliu South Street, Chaoyang District, Beijing, 100022, China.
Abstract:
Casein kinase 2 alpha 1 (CSNK2A1) is a known oncogene, but its role in the progression of colorectal cancer (CRC) remain undefined. Here, we investigated the effects of CSNK2A1 during CRC development. In the current study, CSNK2A1 expression in the colorectal cancer cell lines (HCT116, SW480, HT29, SW620 and Lovo) vs. normal colorectal cell line (CCD841 CoN) were compared via RT-qPCR and western blotting. The role of CSNK2A1 on CRC growth and metastases were investigated through Transwell assay. Immunofluorescence analysis was used to investigate the expression of EMT-related proteins. The association between P300/H3K27ac and CSNK2A1 were analyzed using UCSC bioinformatics and Chromatin-immunoprecipitation (Ch-IP) assays. Results revealed that both the mRNA and protein levels of CSNK2A1 in HCT116, SW480, HT29, SW620 and Lovo cells were upregulated. Additionally, P300-mediated H3K27ac activation at the CSNK2A1 promoter was found to drive the increase in CSNK2A1 expression. Transwell assay showed that CSNK2A1 overexpression increased the migration and invasion of HCT116 and SW480 cells, which decreased following CSNK2A1 silencing. CSNK2A1 was also found to facilitate EMT in HCT116 cells, evidenced by the increases of N-cadherin, Snail and Vimentin expression, and loss of E-cadherin. Importantly, the levels of p-AKT-S473/AKT, p-AKT-T308/AKT, and p-mTOR/mTOR in cells overexpressing CSNK2A1 were high, but significantly decreased following CSNK2A silencing. The PI3K inhibitor BAY-806946 could reverse the increase in p-AKT-S473/AKT, p-AKT-T308/AKT, p-mTOR/mTOR induced by CSNK2A1 overexpression and suppress CRC cell migration and invasion. In conclusion, we report a positive feedback mechanism through which P300 enhances CSNK2A1 expression and accelerates CRC progression through the activation of the PI3K-AKT-mTOR axis.
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