Epigenetic plasticity potentiates a rapid cyclical shift to and from an aggressive cancer phenotype

• Published in: International journal of cancer 2020-06, Vol.146 (11), p.3065-3076
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Bladder cancer; Cancer; cancer plasticity; cancer stem‐like cells; Cell adhesion & migration; Cell cycle; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell Plasticity - genetics; Chromatin; Chromatin - metabolism; chromatin accessibility; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - genetics; Drug resistance; Drug Resistance, Neoplasm - genetics; E2F; E2F3 Transcription Factor - genetics; E2F3 Transcription Factor - metabolism; Epigenetics; Gene Expression Regulation, Neoplastic - genetics; Genotype & phenotype; Humans; Invasiveness; Medical research; Neoplasm Invasiveness - genetics; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Phenotypes; Plasticity; Promoter Regions, Genetic - genetics; Tumor cells; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32904

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. What's new? Cancer cells can cycle in and out of an aggressive cancer stem cell‐like state but mechanisms controlling this process are unknown. Here the authors find that these transitions occur at least in part via epigenetic alterations that drive an aggressive, drug‐resistant phenotype. These findings underscore cancer cells' capacity for rapid, adaptive phenotypic shifts that do not require driver mutations and may offer new therapeutic opportunities in the future.