Low doses of decitabine improve the chemotherapy efficacy against basal-like bladder cancer by targeting cancer stem cells

Abstract

Low dose treatment with the DNA methylation inhibitor decitabine has been shown to be applicable for the management of certain types of cancer. However, its antitumor effect and mechanisms are context dependent and its activity has never been systematically studied in bladder cancer treatment. We used mouse models, cultured cell lines and patient-derived xenografts to demonstrate that low dose decitabine treatment remarkably enhanced the effects of cisplatin and gemcitabine on basal-like bladder cancer both in vivo and in vitro. Genetic lineage tracing revealed that the stemness of a bladder cancer stem cell population was inhibited by decitabine treatment in mice. These effects were accompanied by decreases in genome-wide DNA methylation, gene re-expression, and changes in key cellular regulatory pathways such as STAT3 signaling. These results indicate that this DNA-demethylating reagent is a promising therapeutic approach for basal-like bladder cancer treatment.

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Data availability

The authors declare that all relevant data are available within the article and its Supplementary information files or from the corresponding author upon reasonable request. The MEDIP-sequencing and RNA-sequencing datasets have been submitted to the NCBI database under the accession number GSE113537 and SRP148541.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81872313 and 81672776 to YL, 31501838 to XHZ).

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YL, DC, and JL conceived ideas and experimental design. MW, MC, HZ, FZ, YZ, Yu Liang, and XZ performed the experiments. LS and HZ. provided clinical samples and aided in immunohistochemical analysis, YJ and SL helped with mouse strains and manuscript preparation, ZL and QG helped analyse data and figures. YL and DC wrote the manuscript.

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Correspondence to Demeng Chen or Jiong Li or Yang Li.

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Wu, M., Sheng, L., Cheng, M. et al. Low doses of decitabine improve the chemotherapy efficacy against basal-like bladder cancer by targeting cancer stem cells. Oncogene 38, 5425–5439 (2019). https://doi.org/10.1038/s41388-019-0799-1

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