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bioRxiv · 10.1101/2022.10.28.514256

The DEAD-box protein p68 and B-catenin: the crucial regulators of FOXM1 gene expression in arbitrating colorectal cancer

TABASSUM, S.·BASU, M.·Ghosh, M.
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Abstract

Forkhead box M1 (FOXM1), a vital member of the Forkhead box family of transcription factors, helps in mediating oncogenesis. However, limited knowledge exists regarding the mechanistic insights into the FOXM1 gene regulation. p68, an archetypal member of the DEAD-box family of RNA helicases, shows multifaceted action in cancer progression by arbitrating RNA metabolism and transcriptionally coactivating transcription factors. Here, we report a novel mechanism of alliance between p68 and the Wnt/{beta}-catenin pathway in regulating FOXM1 gene expression and driving colon carcinogenesis. Initial bioinformatic analyses highlighted elevated expression levels of FOXM1 and p68 in colorectal cancer datasets. Immunohistochemical assays confirmed that FOXM1 showed a positive correlation with p68 and {beta}-catenin in both normal and colon carcinoma patient samples. Overexpression of p68 and {beta}-catenin increased the protein and mRNA expression profiles of FOXM1, and the converse correlation occurred during downregulation. Mechanistically, overexpression and knockdown of p68 and {beta}-catenin elevated and diminished FOXM1 promoter activity respectively. Additionally, Chromatin immunoprecipitation assay demonstrated the occupancy of p68 and {beta}-catenin at the TCF4/LEF binding element (TBE) sites on the FOXM1 promoter. Thiostrepton delineated the effect of FOXM1 inhibition on cell proliferation and migration. Colony formation assay, migration assay, and cell cycle data reveal the importance of the p68/{beta}-catenin/FOXM1 axis in oncogenesis. Collectively, our study mechanistically highlights the regulation of FOXM1 gene expression by p68 and {beta}-catenin in colorectal cancer.

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TABASSUM, S., BASU, M., Ghosh, M.. 2022-10-28. The DEAD-box protein p68 and B-catenin: the crucial regulators of FOXM1 gene expression in arbitrating colorectal cancer. https://doi.org/10.1101/2022.10.28.514256

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