Abstract
Pre-B-cell leukemia transcription factor 3 (PBX3) is a member of the PBX family and contains a highly conserved homologous domain. PBX3 is involved in the progression of gastric cancer, colorectal cancer, and prostate cancer; however, the detailed mechanism by which it promotes tumor growth remains to be elucidated. Here, we found that PBX3 silencing induces the expression of the cell cycle regulator p21, leading to an increase in colorectal cancer (CRC) cell apoptosis as well as suppression of proliferation and colony formation. Furthermore, we found that PBX3 is highly expressed in clinical CRC patients, in whom p21 expression is aberrantly low. We found that the regulation of p21 transcription by PBX3 occurs through the upstream regulator of p21, the tumor suppressor p53, as PBX3 binds to the p53 promoter and suppresses its transcriptional activity. Finally, we revealed that PBX3 regulates tumor growth through regulation of the p53/p21 axis. Taken together, our results not only describe a novel mechanism regarding PBX3-mediated regulation of tumor growth but also provide new insights into the regulatory mechanism of the tumor suppressor p53.
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Acknowledgements
We thank Dr. Bert Vogelstein (School of Medicine, Johns Hopkins University) for kindly providing wild-type and p53-null HCT116p53null cell lines. This work was supported by grants from the National Natural Science Foundation of China (11832008, 31871367, and 81872273); the Natural Science Foundation of Chongqing (cstc2018jcyjAX0411 and cstc2018jcyjAX0374); and the Fundamental Research Funds for the Central Universities (2019CDQYSW010).
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VK and SRW conceived the project, analyzed and interpreted the experimental results; VK designed the most experiments of the project and wrote the manuscript. WFL and AH performed most of the experiments. YT and PH performed part of plasmid constructions and cell counting assay. GBS analyzed part of the data and provided part of the material. MM designed shRNA target sites and analyzed part of the data.
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Li, Wf., Herkilini, A., Tang, Y. et al. The transcription factor PBX3 promotes tumor cell growth through transcriptional suppression of the tumor suppressor p53. Acta Pharmacol Sin 42, 1888–1899 (2021). https://doi.org/10.1038/s41401-020-00599-9
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DOI: https://doi.org/10.1038/s41401-020-00599-9
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