Abstract
Colorectal cancer (CRC) is commonly associated with aberrant transcription regulation, but characteristics of the dysregulated transcription factors in CRC pathogenesis remain to be elucidated. In the present study, core-binding factor β (CBFβ) is found to be significantly upregulated in human CRC tissues and correlates with poor survival rate of CRC patients. Mechanistically, CBFβ is found to promote CRC cell proliferation, migration, invasion, and inhibit cell apoptosis in a RUNX2-dependent way. Transcriptome studies reveal that CBFβ and RUNX2 form a transcriptional complex that activates gene expression of OPN, FAM129A, and UPP1. Furthermore, CBFβ significantly promotes CRC tumor growth and live metastasis in a mouse xenograft model and a mouse liver metastasis model. In addition, tumor-suppressive miR-143/145 are found to inhibit CBFβ expression by specifically targeting its 3′-UTR region. Consistently, an inverse correlation between miR-143/miR-145 and CBFβ expression levels is present in CRC patients. Taken together, this study uncovers a novel regulatory role of CBFβ-RUNX2 complex in the transcriptional activation of OPN, FAM129A, and UPP1 during CRC development, and may provide important insights into CRC pathogenesis.
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Data availability
All datasets on which the conclusions of the paper rely are available to readers. The raw data for transcriptome sequencing and ChIP-seq can be accessible at NCBI Gene Expression Omnibus (GEO accession number GSE154876).
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Acknowledgements
We wish to thank Guangxin Zhou for support with clinical sample collection and pathological diagnosis.
Funding
This work was supported by the National Natural Science Foundation of China (31900458, 31870821, 81972267, 31771550, 81973273, 81673380, 31571458), the Natural Science Foundation of Jiangsu Province (BK20190308), the National Key Research and Development Program of China (2017YFC0909700), and the Fundamental Research Funds for the Central Universities (020814380145, 020814380169).
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The author contribution is as follows: CW, ZS, YZ, ML, and JZ conducted the experiments and analyzed the data. CW, ZH, and JC designed the experiment, and CW, ZH, and JC wrote the manuscript. JC and JZ supervised the study. All authors have given approval to the final version of the manuscript.
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Wang, C., Shi, Z., Zhang, Y. et al. CBFβ promotes colorectal cancer progression through transcriptionally activating OPN, FAM129A, and UPP1 in a RUNX2-dependent manner. Cell Death Differ 28, 3176–3192 (2021). https://doi.org/10.1038/s41418-021-00810-2
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DOI: https://doi.org/10.1038/s41418-021-00810-2
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