Xu Tong, Li Hong-Tao, Wei Jenny, Li Meng, Hsieh Tien-Chan, Lu Yi-Tsung, Lakshminarasimhan Ranjani, Xu Rong, Hodara Emmanuelle, Morrison Gareth, Gujar Hemant, Rhie Suhn Kyong, Siegmund Kimberly, Liang Gangning, Goldkorn Amir
Division of Medical Oncology, Department of Internal Medicine, University of Southern California Keck School of Medicine and Norris Comprehensive Cancer Center, Los Angeles, CA.
Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Int J Cancer. 2020 Jun 1;146(11):3065-3076. doi: 10.1002/ijc.32904. Epub 2020 Feb 22.
Highly tumorigenic, drug-resistant cancer stem-like cells drive cancer progression. These aggressive cells can arise repeatedly from bulk tumor cells independently of mutational events, suggesting an epigenetic mechanism. To test this possibility, we studied bladder cancer cells as they cyclically shifted to and from a cancer stem-like phenotype, and we discovered that these two states exhibit distinct DNA methylation and chromatin accessibility. Most differential chromatin accessibility was independent of methylation and affected the expression of driver genes such as E2F3, a cell cycle regulator associated with aggressive bladder cancer. Cancer stem-like cells exhibited increased E2F3 promoter accessibility and increased E2F3 expression that drove cell migration, invasiveness and drug resistance. Epigenetic interference using a DNA methylation inhibitor blocked the transition to a cancer stem-like state and reduced E2F3 expression. Our findings indicate that epigenetic plasticity plays a key role in the transition to and from an aggressive, drug-resistant phenotype.
高度致瘤、耐药的癌症干细胞样细胞推动癌症进展。这些侵袭性细胞可独立于突变事件从大量肿瘤细胞中反复产生，提示存在一种表观遗传机制。为验证这种可能性，我们研究了膀胱癌细胞在往返癌症干细胞样表型过程中的周期性转变，发现这两种状态呈现出不同的DNA甲基化和染色质可及性。大多数差异染色质可及性独立于甲基化，并影响驱动基因如E2F3的表达，E2F3是一种与侵袭性膀胱癌相关的细胞周期调节因子。癌症干细胞样细胞表现出E2F3启动子可及性增加以及E2F3表达增加，从而驱动细胞迁移、侵袭和耐药。使用DNA甲基化抑制剂进行表观遗传干扰可阻断向癌症干细胞样状态的转变并降低E2F3表达。我们的研究结果表明，表观遗传可塑性在向侵袭性、耐药表型转变以及从该表型转变的过程中起关键作用。
