Department of Genetics, School of Life Science, Anhui Medical University, Hefei, Anhui, 230031, China.
Department of Urology, Huadong Hospital, Fudan University, Shanghai, 200040, China.
Oncogene. 2019 Jul;38(27):5425-5439. doi: 10.1038/s41388-019-0799-1. Epub 2019 Mar 27.
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.
低剂量的 DNA 甲基化抑制剂地西他滨治疗已被证明适用于某些类型癌症的治疗。然而，其抗肿瘤作用和机制是依赖于具体情况的，其在膀胱癌治疗中的活性从未被系统研究过。我们使用小鼠模型、培养细胞系和患者来源的异种移植瘤来证明，低剂量地西他滨治疗显著增强了顺铂和吉西他滨对基底样膀胱癌的体内和体外疗效。遗传谱系追踪显示，地西他滨处理抑制了小鼠膀胱癌干细胞群的干性。这些作用伴随着全基因组 DNA 甲基化的减少、基因重新表达以及关键细胞调节途径（如 STAT3 信号通路）的变化。这些结果表明，这种去甲基化试剂是基底样膀胱癌治疗的一种有前途的治疗方法。
