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

Tong Xu, Hong Tao Li, Jenny Wei, Meng Li, Tien Chan Hsieh, Yi Tsung Lu, Ranjani Lakshminarasimhan, Rong Xu, Emmanuelle Hodara, Gareth Morrison, Hemant Gujar, Suhn Kyong Rhie, Kimberly Siegmund, Gangning Liang, Amir Goldkorn

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)3065-3076
Number of pages12
JournalInternational Journal of Cancer
Volume146
Issue number11
DOIs
StatePublished - 1 Jun 2020
Externally publishedYes

Keywords

  • E2F
  • cancer plasticity
  • cancer stem-like cells
  • chromatin accessibility
  • drug resistance

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